Interstitial photodynamic therapy

ABSTRACT

A method of administering interstitial photodynamic therapy to a target region of a patient may include receiving information associated with the target region, an initial photosensitizer concentration, a plurality of initial photosensitizer photokinetic rate parameters, and a threshold treatment dose for a photosensitizer, the threshold treatment dose being a threshold photodynamic therapy-dose or a threshold reactive oxygen species dose. A location in the target region for inserting at least one interstitial treatment fiber to deliver the treatment light, and initial values for treatment light transmission is determined. Computational spatial elements are determined for the target region and for the location of emitting surfaces of the at least one interstitial treatment fiber, and a light fluence rate for delivering treatment light to each of the computational spatial elements. A treatment dose is determined based on the light fluence rate, the plurality of photosensitizer photokinetic rate parameters, and a photokinetic rate equation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of International Patent Application No.PCT/US2021/045341 filed on Aug. 10, 2021, which claims the benefit ofpriority to U.S. Provisional Application No. 63/066,895, filed on Aug.18, 2020, the entirety of each is incorporated herein by reference forall purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under SBIR grant numberR44CA213654 awarded by the National Cancer Institute of the NationalInstitutes of Health. The government has certain rights in theinvention.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to the field of interstitialphotodynamic therapy (I-PDT) and related methods and systems fortreatment planning.

BACKGROUND

Photodynamic therapy (PDT) is a treatment to kill cancerous cells,diseased cells or harmful bacteria that involves therapeuticphoto-chemical interaction of light, photosensitizer (PS) and oxygenwithin tumor cells, diseased cells or harmful bacteria (See e.g.MacDonald et. al., “Basic principles of photodynamic therapy,” J. Nat.Cancer Inst. (1998) 90, 889-905; and Wilson et. al. “The physics ofphotodynamic therapy,” Phys. Med. Biol. (1986) 31, 327-360.). In PDT, aPS is injected into the body or a PS prodrug is applied superficiallyand may accumulate at higher PS concentrations in diseased tissuecompared to normal tissue. Ideally PDT will generate the reactivespecies only within the target volume, leading to damage of the tumor ordiseased tissues, while minimizing damage to surrounding normal tissue.Unlike chemotherapy, PDT does not cause systemic toxicities, and unlikeradiation therapy it does not cause cumulative damage in the localtreatment area. It should be noted that PDT is used in many applicationsin addition to cancer, such as oral cavity disease, blood productspurification, cardiovascular diseases, autoimmune diseases, bacterial orviral infections, eye diseases and skin diseases.

The numerous PDT applications are characterized by multiple geometries.Most can be classified as consisting of interstitial, surface(superficial) or intracavitary illumination. The use of interstitialillumination (I-PDT) using optical fibers for PDT includes prostate andhead and neck cancers, among others. The use of surface illumination forPDT includes, but is not limited to, skin disease, skin cancer andbacterial or viral infections. The use of intracavitary illumination ofthe interior surface of a cavity for PDT includes, but is not limitedto, applications such as oral cavity disease or cancer, disease orcancer of the gastrointestinal or respiratory tracts, thoracic cavitymalignancies, bladder cancer and other cancers such as brain cancerswhere resection (removal) of primary tumors leaves a cavity. The abilityof PDT to spare surrounding critical normal structures and betterhealing after treatment distinguish the benefit of PDT compared to otherlocalized therapeutic approaches, such as surgical resection (excision)or tissue X-ray radiation.

While I-PDT has demonstrated strong clinical efficacy data in somecases, I-PDT treatment planning remains rudimentary for most clinicalapplications. Ideally, methods and systems for I-PDT treatment planningshould be carried out via an established deterministic process which isbased on the target region shape and properties and a soundcomputational model of the treatment. Conventionally, I-PDT treatmentplanning utilizes light dose (measured, for example, in J/cm²) as thedosimetry parameter. However, such planning neglects many importanttreatment factors such as the concentration of the PS, the reactionkinetics of the PS resulting in PS photobleaching, the tissue opticalproperties, the initial oxygen concentration in the target region, theoxygen flow rate into the target region and the quantitative formationof the reactive oxygen species, denoted as ROS.

Singlet oxygen, ¹O₂, is the primary cytotoxic ROS that is responsiblefor cell death in Type II PDT, although other ROS can also be involvedin Type I PDT. In particular, conventional I-PDT treatment planningusing light dose neglects these important factors that are needed andutilized in determining a much more accurate PDT-dose or a much moreaccurate reactive oxygen species dose, [ROS]_(dose). PDT-dose, usuallyexpressed in μM J/cm², for example, is defined as the time integral ofthe product of the fluence rate ϕ times the local PS concentration.[ROS]_(dose) is the concentration of reactive oxygen species producedduring treatment. PDT-dose and [ROS]_(dose) also depend on the fluencerate (i.e., light fluence rate or light intensity or irradiance measuredin mW/cm², for example) and the treatment time, which are additionaltreatment parameters. Inadequate treatment planning that does not takeinto account the concentration and photokinetics of the PS or theconcentration and photokinetics of ROS can lead to increased rates ofunder- or over-treatment that manifest clinically as local recurrence ofcancer or disease or unnecessary local cell death.

SUMMARY

The embodiments disclosed herein are proposed to address the issues withI-PDT disclosed herein. The proposed new and improved treatment planningmethods and systems are accurate for any target region shape, variouslight transport parameters and various photokinetic parameters. BothPDT-dose and [ROS]_(dose) depend on parameters such as PS photokineticrate parameters, the initial PS concentration, PS photobleaching, tissueoptical properties and changes in the tissue oxygen concentration duringI-PDT. The embodiments of the present disclosure stem from therealization that prior art treatment planning methods that thatcalculate only light dose do not account for these parameters.

Some of the improved treatment planning methods and systems utilize, forexample, Monte Carlo (MC) or Finite Element (FE) methods to initiallycalculate fluence rates for all portions of the target region, which isfollowed by photokinetic simulations to ensure that the entire targetregion receives a threshold PDT-dose or a threshold [ROS]_(dose). It isalso highly desirable to show treating physicians 2D or 3Dvisualizations of the resulting PDT-dose or [ROS]_(dose), preferablyshowing, for example, 3D visualizations of the PDT-dose or [ROS]_(dose)superimposed on 3D images of the target region as well as maps of thelight fluence rate distribution. In particular, it is important to showthe PDT-dose or [ROS]_(dose) at the boundaries of the target region toensure that all diseased or cancerous cells at the boundaries aretreated with at least a threshold PDT-dose or a threshold [ROS]_(dose).

Advantageously, the systems and methods described herein mitigate,alleviate or eliminate one or more deficiencies, disadvantages or issuesin the art by providing optimization of treatment planning forinterstitial photodynamic therapy.

Accordingly, in at least one embodiment, a method of administeringinterstitial photodynamic therapy by delivering treatment dose to atarget region of a patient may include receiving, at a processor,information associated with the target region, an initialphoto-sensitizer concentration, a plurality of initial photosensitizerphotokinetic rate parameters, and a threshold treatment dose for aphotosensitizer, the threshold treatment dose being a thresholdphotodynamic therapy-dose or a threshold reactive oxygen species dose. Alocation in the target region for inserting at least one interstitialtreatment fiber to deliver the treatment light is determined. By theprocessor, initial values for therapeutic light power, and lightemitting length and therapeutic treatment time are determined for the atleast one interstitial treatment fiber. By the processor, computationalspatial elements are determined for the target region and for thelocation of emitting surfaces of the at least one interstitial treatmentfiber, and a fluence rate for delivering treatment light to each of thecomputational spatial elements. By the processor, a treatment dose isdetermined based on the fluence rate, the plurality of photosensitizerphotokinetic rate parameters, and a photokinetic rate equation. By theprocessor, a command is generated for controlling a treatment lightsource to deliver the treatment dose to the target region via the atleast one interstitial treatment fiber.

In accordance with at least one embodiment, a system for delivering atreatment dose to a target region of a patient for interstitialphotodynamic therapy may include a treatment light source coupled to atleast one interstitial treatment fiber. A diagnostic light source iscoupled to at least one interstitial diagnostic fiber. At least oneinterstitial detector detects diagnostic light generated by thediagnostic light source and/or treatment light generated by thetreatment light source and/or photosensitizer fluorescence generated bythe diagnostic light source or the treatment light source. A processoris configured to receive information associated with the target region,an initial photosensitizer concentration, a plurality of initialphotosensitizer photokinetic rate parameters, and a threshold treatmentdose for a photosensitizer, the threshold treatment dose being athreshold photodynamic therapy-dose or a threshold reactive oxygenspecies dose. A location is determined in the target region forinserting the at least one interstitial treatment fiber to deliver thetreatment light. Initial values are determined for therapeutic lightpower, and light emitting length and therapeutic treatment time for theat least one interstitial treatment fiber. Computational spatialelements are determined for the target region and for the location ofemitting surfaces of the at least one interstitial treatment fiber, anda fluence rate for delivering treatment light to each of thecomputational spatial elements. A treatment dose is determined based onthe fluence rate, the plurality of photosensitizer photokinetic rateparameters, and a photokinetic rate equation. A command is generated forcontrolling the treatment light source to deliver via the at least oneinterstitial treatment fiber the treatment dose to the target region.

In an aspect of the present application, a method of planning aninterstitial photodynamic therapy treatment dose to be delivered totarget region of a patient may include receiving, at a processor,information associated with the target region, an initialphoto-sensitizer concentration, a plurality of initial photosensitizerphotokinetic rate parameters, and a threshold treatment dose for aphotosensitizer, the threshold treatment dose being a thresholdphotodynamic therapy-dose or a threshold reactive oxygen species dose. Alocation in the target region for inserting at least one interstitialtreatment fiber to deliver the treatment light is determined. By theprocessor, initial values for therapeutic light power, and lightemitting length and therapeutic treatment time are determined for the atleast one interstitial treatment fiber. By the processor, computationalspatial elements are determined for the target region and for thelocation of emitting surfaces of the at least one interstitial treatmentfiber, and a fluence rate for delivering treatment light to each of thecomputational spatial elements. By the processor, a treatment dose isdetermined based on the fluence rate, the plurality of photosensitizerphotokinetic rate parameters, and a photokinetic rate equation.

In accordance with at least one embodiment, a system for planning aninterstitial photodynamic therapy may include a non-transitorycomputer-readable memory to store instructions and a processor toexecute the instructions stored on the memory. The instructions causethe processor to receive information associated with the target region,an initial photosensitizer concentration, a plurality of initialphotosensitizer photokinetic rate parameters, and a threshold treatmentdose for a photosensitizer, the threshold treatment dose being athreshold photodynamic therapy-dose or a threshold reactive oxygenspecies dose. A location is determined in the target region forinserting the at least one interstitial treatment fiber to deliver thetreatment light. Initial values are determined for therapeutic lightpower, and light emitting length and therapeutic treatment time for theat least one interstitial treatment fiber. Computational spatialelements are determined for the target region and for the location ofemitting surfaces of the at least one interstitial treatment fiber, anda fluence rate for delivering treatment light to each of thecomputational spatial elements. A treatment dose is determined based onthe fluence rate, the plurality of photosensitizer photokinetic rateparameters, and a photokinetic rate equation.

In accordance with at least one embodiment, a non-transitorymachine-readable medium storing instructions to cause one or moreprocessors to perform operations including receiving, at a processor,information associated with the target region, an initialphoto-sensitizer concentration, a plurality of initial photosensitizerphotokinetic rate parameters, and a threshold treatment dose for aphotosensitizer, the threshold treatment dose being a thresholdphotodynamic therapy-dose or a threshold reactive oxygen species dose. Alocation in the target region for inserting at least one interstitialtreatment fiber to deliver the treatment light is determined. By theprocessor, initial values for therapeutic light power, and lightemitting length and therapeutic treatment time are determined for the atleast one interstitial treatment fiber. By the processor, computationalspatial elements are determined for the target region and for thelocation of emitting surfaces of the at least one interstitial treatmentfiber, and a fluence rate for delivering treatment light to each of thecomputational spatial elements. By the processor, a treatment dose isdetermined based on the fluence rate, the plurality of photosensitizerphotokinetic rate parameters, and a photokinetic rate equation.

Additional features and advantages of the subject technology will be setforth in the description below, and in part will be apparent from thedescription, or may be learned by practice of the subject technology.The advantages of the subject technology will be realized and attainedby the structure particularly pointed out in the written description andembodiments hereof as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features of illustrative embodiments of the present disclosureare described below with reference to the drawings. The illustratedembodiments are intended to illustrate, but not to limit, the presentdisclosure. The drawings contain the following figures:

FIG. 1 is a Jablonski diagram for formation of singlet oxygen and thereaction of singlet oxygen with target cells and with thephotosensitizer as in type II photodynamic therapy.

FIG. 2 schematically depicts a method for generating an interstitialphotodynamic therapy plan.

FIG. 3 schematically depicts another method for generating aninterstitial photodynamic therapy plan.

FIG. 4 schematically depicts a system for generating an interstitialphotodynamic therapy plan.

FIG. 5 schematically depicts another system for generating aninterstitial photodynamic therapy plan.

FIG. 6 is another schematic diagram of a system for generating aninterstitial photodynamic therapy plan.

FIG. 7 is a schematic diagram of a system for delivering interstitialphotodynamic therapy along with a cross-sectional view of a targetregion.

FIG. 8 is a view of a target region.

FIG. 9 is a view of a target region with a hole.

FIG. 10 is a view of a target region with a hole showing surface facesand nodes of a tetrahedral mesh.

FIG. 11 is a partial view of a target region with a hole showing surfacefaces and nodes of a tetrahedral mesh, including surface faces and nodesof tetrahedral mesh in the hole.

FIG. 12 shows a portion of a target region that receives a thresholdfluence rate.

FIG. 13 shows a cross sectional view of a portion of a target region anda portion of the surface of the hole that receive a threshold fluencerate.

FIG. 14 shows a portion of a target region that receives a thresholdPDT-dose.

FIG. 15 shows a cross sectional view of a portion of a target region anda portion of the surface of the hole that receive a threshold PDT-dose.

FIG. 16 shows a portion of a target region that receives a thresholdsinglet oxygen or ROS dose.

FIG. 17 shows a cross sectional view of a portion of a target region anda portion of the surface of the hole that receive a threshold singletoxygen or ROS dose.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a full understanding of the subject technology. Itshould be understood that the subject technology may be practicedwithout some of these specific details. In other instances, well-knownstructures and techniques have not been shown in detail so as not toobscure the subject technology.

Further, while the present description sets forth specific details ofvarious embodiments, it will be appreciated that the description isillustrative only and should not be construed in any way as limiting.Furthermore, various applications of such embodiments and modificationsthereto, which may occur to those who are skilled in the art, are alsoencompassed by the general concepts described herein.

PDT Dosimetry Overview

PDT dosimetry involves determining the treatment dose delivered tocancerous, diseased or normal tissue at a fixed or variable fluencerate, which is defined as the induced or delivered fluence rate (i.e.,light intensity or irradiance in mW/cm²) at each point in the targetvolume. There are three types of primary treatment dose metrics that areknown to be used for PDT: (1) light dose (fluence) usually expressed injoules per centimeter squared (J/cm²), for example, which is equal thefluence rate (mW/cm² or mJ/(s cm²) times the time in seconds (s); (2)PDT-dose, usually expressed in μM J/cm², for example, which is definedas the time integral of the product of the local PS concentration timesthe fluence rate ϕ; and (3) reactive oxygen species dose, [ROS]_(dose).For type II PDT, the reactive oxygen species dose, [ROS]_(dose) is equalto the reactive singlet oxygen dose, [¹O₂]_(dose). For each type ofdose, a threshold dose is needed to kill cancer cells.

Light Dose

Standard PDT treatment planning of a treatment delivery protocolinvolves giving each patient the same total light dose (i.e. energy orincident fluence per area, J/cm²), determined for a particular type ofcancer, irrespective of variations of PS concentration or othervariables within a single target region or variations among differentpatients. An example of a light dose is, for example, 100 J/cm²,although other higher or lower light doses have been previouslyutilized. Depending on other conditions such as PS concentration andoxygen intake rate, the conventional light dose may or may not result inan effective PDT-dose or [ROS]_(dose) or in an effective treatment.There is a threshold light dose needed to kill cells. This threshold canvary depending on treatment conditions such as the type of PS, the PSconcentration, the initial oxygen concentration in the tissue, theoxygen flow rate delivered by blood flow to the tissue and the tissueoptical properties. This variability in treatment conditions can lead tounreliable treatment results.

Some relevant surface PDT publications that include a thresholdtreatment light dose are: Sheng et. al. “Reactive oxygen speciesexplicit dosimetry to predict local tumor control for Photofrin mediatedphotodynamic therapy,” Proc. SPIE 10860, 108600V (2019); and Sheng etal., “Reactive oxygen species explicit dosimetry to predict tumor growthfor benzoporphyrin derivative-mediated vascular photodynamic therapy”,J. Biomedical Optics 25(6), 063805 (2020). An I-PDT publication forthreshold light dose is Shafirstein et. al., “Irradiance controlsphotodynamic efficacy and tissue heating in experimental tumours:implication for interstitial PDT of locally advanced cancer”, BritishJournal of Cancer, 19, 1191-1199 (2018). Some examples of thresholdlight dose for animals are listed in TABLE 1. It is expected that athreshold light dose is also needed for treating human cancer tissue.See, for example, Davidson et al., “Treatment planning and dose analysisfor interstitial photodynamic therapy of prostate cancer,” Phys. Med.Biol. 54 (2009) 2293-2313.

Without wishing to be bound by theory, the threshold doses may bereliable if the treated tissue has sufficient PS concentration andsufficient oxygen concentration (i.e. any oxygen concentration valueabove a threshold value that can kill target cells) to enable PDT. Ifthe PS concentration or the oxygen concentration are too low, the targetcancerous tissues may not be killed.

TABLE 1 Photosensitizer Animal Threshold Light Dose [J/cm²] PhotofrinMice Approx. 100 (Sheng et. al., 2019) Mice ≥45 (Shafirstein et. al.,2018) Rabbits ≥45 (Shafirstein et. al., 2018) BPD Mice Approx. 40(vascular, Sheng et. al., 2020) Tookcad Human >23 (Davidson et.al.,2009) prostatePDT-Dose

PDT-dose, usually expressed in μM J/cm², for example, is defined as thetime integral of the product of the fluence rate ϕ times the local PSconcentration. PDT-dose is usually more accurate for PDT treatmentdosimetry than light dose because it takes into account theconcentration of PS in the tissue, whereas light dose does not. Forexample, if the concentration of PS is very low or zero, no cancer willbe killed even at a high light dose. Although PDT-dose will take the PSconcentration into account, PDT-dose does not take into account thelocal oxygen concentration. If the oxygen concentration is too low,cancer cells will not be killed even for a high PDT-dose. There is athreshold PDT-dose needed to kill cells. This threshold can varydepending on conditions such as the type of PS, the PS concentration,the initial oxygen concentration in the tissue, the oxygen flow ratedelivered by blood flow to the tissue and the tissue optical properties.Some relevant surface PDT publications that include a threshold PDT-doseare: Kim, et al; “Evaluation of singlet oxygen explicit dosimetry forpredicting treatment outcomes of benzoporphyrin derivative monoacid ringA-mediated photodynamic therapy”; J Biomedical Optics, 22(2), 028002(2017); Penjweini et al; “Evaluation of the2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediatedphotodynamic therapy by macroscopic singlet oxygen modeling”; J.Biophotonics 9(11-12), 1344-1354 (2016); Sheng et. al. “Reactive oxygenspecies explicit dosimetry to predict local tumor control for Photofrinmediated photodynamic therapy,” Proc. SPIE 10860, 108600V (2019); Sheng,T et al; “Reactive oxygen species explicit dosimetry to predict tumorgrowth for benzoporphyrin derivative-mediated vascular photodynamictherapy”, J. Biomedical Optics 25(6), 063805 (2020)

Some surface PDT examples of threshold PDT-dose for animals are listedin TABLE 2. It is expected that a threshold PDT-dose is also needed fortreating human cancer tissue. The threshold doses are only reliable ifthe treated tissue has sufficient oxygen concentration to enable PDT.

TABLE 2 Threshold PDT-dose Photosensitizer Animal (μM J/cm²) PhotofrinMice 439 (Sheng et. al., 2019) BPD Mice 58 ± 12 (Kim et. al., 2017) 7.5(vascular, Sheng et. al., 2020) HPPH Mice 52.62 ± 14.9 (Penjweini et.al., 2016)Reactive Oxygen Species Dose, [ROS]_(dose), or Reactive Singlet OxygenDose, [¹O₂]_(dose)

Recent experimental surface PDT work on tumors in mice indicates thatthe reactive oxygen species treatment dose, [ROS]_(dose), or, inparticular, the reactive singlet oxygen dose, [¹O₂]_(dose), generated bythe treatment light is more important than the conventional total lightdose. See for example: Sheng, T. et al; “Reactive oxygen speciesexplicit dosimetry to predict tumor growth for benzoporphyrinderivative-mediated vascular photodynamic therapy”, J. Biomedical Optics25(6), 063805 (2020); Penjweini, R. et al; “Evaluation of the2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediatedphotodynamic therapy by macroscopic singlet oxygen modeling”; J.Biophotonics 9(11-12), 1344-1354 (2016) and Penjweini, R. et. al.;In-vivo outcome study of HPPH medicated PDT using singlet oxygenexplicit dosimetry (SOED), Proc. of SPIE 2015; Vol. 9308, 93080N. Thesame light dose may result in differing amounts of generated singletoxygen or other ROS depending on the treatment conditions such as thefluence rate and oxygen intake from blood flow. It has been found inmice that a threshold [ROS]_(dose) should be reached during PDTtreatment to successfully kill cancer cells. See, for example, Sheng etal, “Reactive oxygen species explicit dosimetry to predict tumor growthfor benzoporphyrin derivative-mediated vascular photodynamic therapy”,J. Biomedical Optics 25(6), 063805 (2020). It is expected that athreshold [ROS]_(dose) or, in particular, a threshold [¹O₂]_(dose) willalso be required to kill cancer cells in humans. This assumption cannotbe directly tested since the experiments that were done on mice cannotbe done on humans. The singlet oxygen threshold dose needed to killcancer will depend on the type of tumor undergoing the treatment.Superficial PDT examples of threshold [¹O₂]_(dose) are shown in TABLE 3,where the data are taken from (a) Zhu et. al; “In-vivo singlet oxygenthreshold doses for PDT”; Photon Lasers Med. 2015; 4(1), 59-71; (b) Qiuet al; “Macroscopic singlet oxygen modeling for dosimetry ofPhotofrin-mediated photodynamic therapy: an in-vivo study”; J.Biomedical Optics, 21(8), 088002 (2016); (c) Kim et al; “Evaluation ofsinglet oxygen explicit dosimetry for predicting treatment outcomes ofbenzoporphyrin derivative monoacid ring A-mediated photodynamictherapy”; J Biomedical Optics, 22(2), 028002 (2017); (d) Penjweini etal; “Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide(HPPH) mediated photodynamic therapy by macroscopic singlet oxygenmodeling”; J. Biophotonics 9(11-12), 1344-1354 (2016). Note that thevalues of threshold [¹O₂]_(dose) in TABLE 3 are labeled [O₂]_(rx) in thepublications.

TABLE 3 Photosensitizer Animal Threshold [¹O₂]_(dose) (mM) PhotofrinMice 0.56 ± 0.26 (Zhu et. al., 2015) >1.0 (Qiu et. al., 2016) BPD Mice0.72 ± 0.21 (Zhu et. al., 2015) 0.98 ± 012 (Kim et. al. 2017) HPPH Mice0.98 ± 0.11 (Penjweini et. al., 2016)Fluence Rate as a Secondary Dose Metric

In the case of using light dose as the primary metric, it has been foundthat a secondary dose metric is also necessary. It was found that athreshold fluence dose rate ϕ_(T) (i.e. threshold irradiance in, forexample, mW/cm²) is necessary to kill cancer in mice and rabbits.Shafirstein et. al., “Irradiance controls photodynamic efficacy andtissue heating in experimental tumours: implication for interstitial PDTof locally advanced cancer”, British Journal of Cancer, 19, 1191-1199(2018). In particular, healing threshold fluence rates (see TABLE 4)have been shown for I-PDT treatment of mice and rabbits using the lightdose as the dose metric.

TABLE 4 Threshold Fluence Rate ϕ_(T) Photosensitizer Animal [mW/cm²]Photofrin Mice  8.4 (Shafirstein et. al., 2018) Rabbits 16.5(Shafirstein et. al., 2018)PDT Treatment Planning

In order to do accurate dosimetry in treatment planning and treatmentdelivery, computer simulations are performed. For superficial PDT andintracavitary PDT only, there exist prior art computer devices andsoftware that can calculate PDT-dose, [¹O₂]_(dose) and PDT treatmentfluence rates, but only for a single fixed treatment light sourceposition. To our knowledge, there are no prior art computer devices andsoftware for I-PDT that utilize photokinetic simulations to calculatePDT-dose or reactive oxygen species dose, [ROS]_(dose), with one or morelight sources.

Input parameters include the treatment light source fluence rate ϕ, thetarget shape, the light source position relative to target shape, theoptical parameters of the target and the PS concentration. Prior artcomputer devices and software for surface PDT are described in Beesonet. al., “Validation of combined Monte Carlo and photokineticsimulations for the outcome correlation analysis of benzoporphyrinderivative-mediated photodynamic therapy on mice,” J. Biomed. Opt 24(3),035006, (2019a), and Beeson et. al. “Validation of Dosie™ combined MonteCarlo and photokinetic simulations for the analysis of HPPH-mediatedphotodynamic therapy on mice,” Proc. SPIE 10860, 108600N (2019b). Thesepublications describe Monte Carlo simulations to determine light doseand treatment fluence rates and photokinetic simulations that use thefluence rate simulations to determine PDT-dose and [¹O₂]_(dose). Anexample of photokinetic simulations to determine [¹O₂]_(dose) follows.

The amount of singlet oxygen [¹O₂] generated during PDT depends on thePS concentration and other parameters such as the amount of oxygen inthe affected tissue, the amount of new oxygen that is being supplied tothe tissue by blood vessels—the oxygen intake rate—the fluence rate(mW/cm²) at the location of the PDT treatment and the treatment time.Note that a given threshold amount of singlet oxygen to kill cancercells can be generated by a wide range of fluence rates and treatmenttimes.

In order to calculate the amount of singlet oxygen generated for eithersuperficial PDT or intracavitary PDT at any point within canceroustissue or on its surface, one must consider two coupled calculations:(1) light transport through the tissue initiated by a given fluence rateincident to the surface of the tumor tissue (also called direct light),where the delivered light inside the tissue has a different fluence rateafter undergoing scattering and absorption by the tissue; and (2) thephotokinetics of the PS interacting with the delivered light, where theinteraction depends on the fluence rate of the delivered light.

The light transport portion of the calculation can be addressed by, forexample, Monte Carlo or finite element (FE) simulations or byapproximate solutions to the diffusion equation. Monte Carlo (MC)methods are a set of randomized computational algorithms particularlysuitable for simulations of complex systems. Distinct from mostdeterministic numerical techniques which produce solutions by solving aset of differential equations, Monte Carlo methods generate solutions byestimating the probability distribution after launching a large numberof independent random trials. (See, for example, Fang et. al., “MonteCarlo simulation of photon migration in 3D turbid media accelerated bygraphics processing units,” Optics Express 17(22), 20178 (2009), Beesonet. al., “Validation of combined Monte Carlo and photokineticsimulations for the outcome correlation analysis of benzoporphyrinderivative-mediated photodynamic therapy on mice,” J. Biomed. Opt 24(3),035006 (2019a), and Beeson et. al. “Validation of Dosie™ combined MonteCarlo and photokinetic simulations for the analysis of HPPH-mediatedphotodynamic therapy on mice,” Proc. SPIE 10860, 108600N (2019b).) Incontrast to MC methods, FE can be used to solve the time-dependent lightdiffusion approximation equation as a boundary value problem withappropriate initial conditions. See, for example, Oakley et al., “A NewFinite Element Approach for Near Real-Time Simulation of LightPropagation in Locally Advanced Head and Neck Tumors Lasers,” Lasers inSurgery and Medicine 47, 60-67 (2015).

One can calculate the total amount of singlet oxygen generated by a PDTtreatment by solving numerically the explicit kinetic rate equations ofthe PDT photo-chemical reactions. FIG. 1 shows Jablonski diagram 10 forType II PDT where single-photon photo-excitation of a photosensitizer(PS) from the ground state S₀ to the excited state S₁ results in theformation of singlet oxygen, ¹O₂, from ground state triplet oxygen, ³O₂.The singlet oxygen then can react and destroy cancer target cells,denoted as A, as well as react and destroy a portion of the PS groundstate S₀. See e.g. Wang et. al; Explicit dosimetry for photodynamictherapy: macroscopic singlet oxygen modeling, J. Biophotonics 2010 June;3(5-6); 304-318). The reactions for Type II PDT can be described by thefollowing set of coupled differential equations (1)-(6). (For Type IPDT, the same set of equations can also be used or different Jablonskidiagram with an alternative set of equations can optionally besubstituted. See, for example Kim et. al.; On the in vivo photochemicalrate parameters for PDT reactive oxygen species modeling, Phys. Med.Biol. 62 (2017) R1-R48.)

In the following equations for Type II PDT, the concentration of theground state of the PS is [S₀], the concentration of the first excitedstate of the PS is [S₁], the concentration of the triplet state of thePS is [T], the concentration of the ground state of oxygen is [³O₂], theconcentration of the excited state of oxygen is [¹O₂], and theconcentration of the cancer target is [A]. The photo-kinetic parametersk₀-k₇, g, δ, and S_(Δ) are defined in TABLE 5.

$\begin{matrix}{\left. {{\left. {\frac{d\left\lbrack S_{o} \right\rbrack}{dt} = {{- {k_{0}\left\lbrack S_{o} \right\rbrack}} - {k_{1}\left\lbrack {}^{1}O_{2} \right.}}} \right\rbrack\left( {\left\lbrack S_{0} \right\rbrack + \delta} \right)} + {{k_{2}\lbrack T\rbrack}\left\lbrack {}^{3}O_{2} \right.}} \right\rbrack + {k_{3}\left\lbrack S_{1} \right\rbrack} + {k_{4}\lbrack T\rbrack}} & (1)\end{matrix}$ $\begin{matrix}{\frac{d\left\lbrack S_{1} \right\rbrack}{dt} = {{\left( {k_{3} + k_{5}} \right)\left\lbrack S_{1} \right\rbrack} + {k_{0}\left\lbrack S_{0} \right\rbrack}}} & (2)\end{matrix}$ $\begin{matrix}{\left. {\frac{d\lbrack T\rbrack}{dt} = {{- {k_{2}\lbrack T\rbrack}\left\lbrack {}^{3} \right.}O_{2}}} \right\rbrack + {k_{4}\lbrack T\rbrack} + {k_{5}\left\lbrack S_{1} \right\rbrack}} & (3)\end{matrix}$ $\begin{matrix}{\left. {\left. {\frac{\left. {d\left\lbrack {}^{3}O_{2} \right.} \right\rbrack}{dt} = {{- S_{\Delta}}{k_{2}\lbrack T\rbrack}\left\lbrack {}^{3}O_{2} \right.}} \right\rbrack + {k_{6}\left\lbrack {}^{1}O_{2} \right.}} \right\rbrack + g} & (4)\end{matrix}$ $\begin{matrix}\left. {\left. {\left. {\left. {\frac{\left. {d\left\lbrack {}^{1}O_{2} \right.} \right\rbrack}{dt} = {{- {k_{1}\left( {\left\lbrack S_{0} \right\rbrack + \delta} \right)}\left\lbrack {}^{1} \right.}O_{2}}} \right\rbrack + {S_{\Delta}{k_{2}\lbrack T\rbrack}\left\lbrack {}^{3}O_{2} \right.}} \right\rbrack - {k_{6}\left\lbrack {}^{1}O_{2} \right.}} \right\rbrack - {{k_{7}\lbrack A\rbrack}\left\lbrack {}^{1}O_{2} \right.}} \right\rbrack & (5)\end{matrix}$ $\begin{matrix}\left. {\frac{d\lbrack A\rbrack}{dt} = {{- {k_{7}\lbrack A\rbrack}\left\lbrack {}^{1} \right.}O_{2}}} \right\rbrack & (6)\end{matrix}$

The system of differential equations (1)-(6) can be solved numerically(See e. g. Zhu et. al; Macroscopic modeling of the singlet oxygenproduction during PDT; Proc. SPIE 2007; Vol. 6427, 642708; and Potaseket. al.; Calculation of singlet oxygen formation from one photonabsorbing photosensitizers used in PDT; Proc. SPIE 2013; Vol. 8568,85681D). However, there are two issues here. First, the rate parameters,k₀-k₇, may not be accurately known for a photosensitizer in livingtissue. Second, since the treatment time scales for the reactions inEquations (1)-(6) range from nanoseconds to thousands of seconds,numerical calculations can take hours to complete which is undesirablefor treatment planning.

To get around these issues, approximate solutions to Equations (1)-(6)have been described. (See e.g. Wang et. al; Explicit dosimetry forphotodynamic therapy: macroscopic singlet oxygen modeling, J.Biophotonics 2010 June; 3(5-6), 304-318) Since the lifetimes of [S₁],[T] and [¹O₂] are short compared to [S₀] and [³O₂], then [S₁], [T] and[¹O₂] are treated as reaching steady state relative to [S₀] and [³O₂].The derivatives in equations (2), (3) and (5) are set equal to zero asshown in equations (7), (8) and (9).

$\begin{matrix}{\frac{d\left\lbrack S_{1} \right\rbrack}{dt} = 0} & (7)\end{matrix}$ $\begin{matrix}{\frac{d\lbrack T\rbrack}{dt} = 0} & (8)\end{matrix}$ $\begin{matrix}{\frac{\left. {d\left\lbrack {}^{1}O_{2} \right.} \right\rbrack}{dt} = 0} & (9)\end{matrix}$

As explained in e.g. Wang et. al; Explicit dosimetry for photodynamictherapy: macroscopic singlet oxygen modeling, J. Biophotonics 2010 June;3(5-6), 304-318, the six Equations (1)-(6) then reduce to the followingthree Equations (10)-(12). One can solve the system of Equations(10)-(12) numerically and determine the total singlet oxygen dose,[¹O₂]_(dose), which is denoted in Wang, K. K. et. al. publication as[¹O₂]_(rx), for Type II PS. Or one can solve for [ROS]_(dose) using theequivalent set of equations as described in Sheng et. al.; Reactiveoxygen species explicit dosimetry to predict tumor growth forbenzoporphyrin derivative-mediated vascular photodynamic therapy, J.Biomed. Opt. 2020; 25(6), 063805 for Type I PS. For simplicity, it canbe assumed that the constant S_(Δ)=0.

$\begin{matrix}{\frac{d\left\lbrack S_{0} \right\rbrack}{dt} = {{- \frac{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack}{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack + \beta}}\left( {\left\lbrack S_{0} \right\rbrack + \delta} \right){\phi\left\lbrack S_{0} \right\rbrack}\xi\sigma}} & (10)\end{matrix}$ $\begin{matrix}{\frac{\left. {d\left\lbrack {}^{3}O_{2} \right.} \right\rbrack}{dt} = {{{- \frac{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack}{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack + \beta}}{\phi\left\lbrack S_{0} \right\rbrack}\xi} + {g\left( {1 - \frac{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack}{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack_{0}}} \right)}}} & (11)\end{matrix}$ $\begin{matrix}{\frac{{d\lbrack{ROS}\rbrack}_{dose}}{dt} = {\xi\frac{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack}{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack + \beta}{\phi\left\lbrack S_{0} \right\rbrack}}} & (12)\end{matrix}$

The total singlet oxygen dose can be found by integrating Equation (12)from time t=0 to the treatment time, T, which gives:

$\begin{matrix}{\lbrack{ROS}\rbrack_{dose} = {{\int}_{0}^{T}\xi\frac{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack}{\left. \left\lbrack {}^{3}O_{2} \right. \right\rbrack + \beta}{\phi\left\lbrack S_{0} \right\rbrack}{dt}}} & (13)\end{matrix}$

The parameters used in Equations (10)-(13) are defined in TABLE 5. Theξ, σ and β parameters are related to the rates k₁-k₇ and [A]. The ξ, σand β parameters can differ for different photosensitizers and can bedetermined experimentally. The fluence rate is denoted as ϕ. Equations(10)-(13) can be (13) solved by standard numerical integrationtechniques (e.g., Runge-Kutta method) when the starting values of the PSconcentration, [S₀ (t=0)], the tissue oxygen concentration, [³O₂ (t=0)],and the oxygen intake rate, g, are specified. A table of kineticparameters for a variety of photosensitizers can be found in Kim et.al.; On the in vivo photochemical rate parameters for PDT reactiveoxygen species modeling, Phys. Med. Biol. 62 (2017) R1-R48.

TABLE 5 Parameter Definition Units k₀ Photon absorption rate of PS perPS s⁻¹ concentration k₁ Bimolecular rate for ¹O₂ reaction s⁻¹μM⁻¹ withPS ground state S₀ k₂ Bimolecular rate of PS triplet T s⁻¹μM⁻¹ statequenching by ³O₂ k₃ Decay rate of PS first excited state S₁ s⁻¹ k₄ Rateof decay of PS triplet state T s⁻¹ k₅ Decay rate of PS first excitedstate S₁ s⁻¹ to triplet state T k₆ ¹O₂ to ³O₂ decay rate s⁻¹ k₇Bimolecular rate of reaction of ¹O₂ s⁻¹μM⁻¹ with cancer target A S_(Δ)Fraction of PS triplet state T to ³O₂ — reactions to produce ¹O₂ δ Lowconcentration correction μM g ³O₂ oxygen intake rate μMs⁻¹ ξ${S_{\Delta}\left( \frac{k_{5}}{k_{5} + k_{3}} \right)}\frac{\varepsilon}{hv}\left( \frac{{k_{7}\lbrack A\rbrack}/k_{6}}{{{k_{7}\lbrack A\rbrack}/k_{6}} + 1} \right)$cm²mW⁻¹s⁻¹ σ k₁/(k₇[A]) μM⁻¹ ε PS extinction coefficient cm⁻¹μM⁻¹ hvEnergy of one photon; h is Planck's Joules constant; v is the photonfrequency β k₄/k₂ μM ϕ Fluence rate mW/cm² [S₀ (t = 0)] Initial PSconcentration at time t = 0 μM [³O₂ (t = 0)] Initial ground state oxygenμM concentration at time t = 0

Some experimentally determined values for the ε, ξ and β parameters fordifferent photosensitizers are listed in TABLE 6. (See e. g. Zhu et. al;In-vivo singlet oxygen threshold doses for PDT; Photon Lasers Med. 2015;4(1), 59-71 and Ong et al, Reactive oxygen species explicit dosimetry(ROSED) of type I photosensitizer; Proc. SPIE: 2018, 10476, 1-10.)

TABLE 6 Parameter (units) Photosensitizer (wavelength) ε (cm⁻¹μM⁻¹)Photofrin (630 nm): 0.0035 mTHPC (650 nm): 0.048 BPD (690 nm): 0.0783Tookad (762 nm) ξ (cm²mW⁻¹s⁻¹) Photofrin: 3.7 × 10⁻³ mTHPC: 30.0 × 10⁻³BPD: 51.0 × 10⁻³ Tookad: 122 × 10⁻³ σ (μM⁻¹) Photofrin: 7.6 × 10⁻⁵mTHPC: 2.97 × 10⁻⁵ BPD: 1.7 × 10⁻⁵ Tookad: 2.6 × 10⁻⁵ β (μM) Photofrin:11.9 mTHPC: 8.7 BPD: 11.9 Tookad: 11.9

The kinetic Equations (10)-(13) are also needed in order to calculatePDT-dose. To calculate PDT-dose, which is defined as the time integralof the product of the fluence rate ϕ times the local PS concentration,one can solve Equation (10) for the PS concentration (i.e. [S₀] inEquation (10)) as a function of time, multiply by the fluence rate ϕ andthen calculate the time integral of the result.

Referring now to FIG. 1 , which shows Jablonski diagram 10 forsingle-photon, photo-excitation of an electron of a photosensitizer (PS)from a ground state S₀ to an excited state S₁, transferring an electronto a triplet state T which undergoes energy transfer from state T tooxygen resulting in the formation of singlet oxygen, ¹O₂, from groundstate triplet oxygen, ³O₂. The singlet oxygen then can react and destroycancer target cells, denoted as A, as well as react and destroy aportion of the PS ground state, which is labeled S₀.

The present disclosure, thus, provides a method for generating aninterstitial photodynamic therapy treatment plan. FIG. 2 depicts anembodiment of the method 100 for treatment planning for optimizing I-PDTtreatment dose delivery to a target region. Advantageously, the method100 establishes a treatment plan that will deliver at least a thresholdtreatment dose over the entire target region and that is also within anacceptable tolerance that will not significantly damage healthy tissueand organs-at-risk. The threshold treatment dose can be a thresholdPDT-dose, a threshold [ROS]_(dose) or a threshold light dose. Preferablythe threshold treatment dose is a threshold PDT-dose or a threshold[ROS]_(dose). The threshold [ROS]_(dose) may be a threshold[¹O₂]_(dose). It is more preferable that each treatment utilizing aprimary threshold PDT-dose or primary threshold [ROS]_(dose) optionallyadds a secondary dose metric, where the secondary dose metric is athreshold fluence rate ϕ needed in order to kill cancer cells or wherethe secondary dose metric is a threshold light dose.

In some embodiments, the method 100 utilizes a computer processor thatreceives input information for the treatment plan and determines atherapeutic dose for a target region in a patient.

At 105, a computer processor receives shape information for the targetregion. The shape of the target region may be obtained using imagingtechniques including, but not limited to, a computed tomography (CT)scan, a positron emission tomography (PET) scan, a magnetic resonanceimaging (MRI) scan, an ultrasound image or a 3D camera image. CT scansand MRI scans, for example, provide slice information about a 3D targetregion such as a tumor. Using commercially-available or open-sourcegeometry processing software packages, one can take the sliceinformation, manually or automatically outline the target region in eachslice, and then construct a 3D representation of the target region.

At 110, the computer processor receives an initial photosensitizerconcentration and initial photosensitizer photokinetic rate parameters.The photosensitizer photokinetic rate parameters will be different fordifferent photosensitizers. A table of photokinetic rate parameters fora variety of photosensitizers can be found, e.g., in Kim et. al.; On thein vivo photochemical rate parameters for PDT reactive oxygen speciesmodeling, Phys. Med. Biol. 62 (2017) R1-R48.

At 115, the computer processor receives threshold treatment doseinformation for the target region. Preferably, the primary thresholdtreatment dose metric is a threshold PDT-dose or a threshold[ROS]_(dose). The threshold [ROS]_(dose) may be a threshold[¹O₂]_(dose). The threshold PDT-dose or the threshold [ROS]_(dose) maybe obtained from prior clinical data or from published or unpublishedresults. It is preferable that each treatment utilizing a primarythreshold PDT-dose or primary threshold [ROS]_(dose) optionally adds asecondary dose metric, where the secondary dose metric is a thresholdfluence rate ϕ needed in order to kill cancer cells or where thesecondary dose metric is a threshold light dose.

The threshold treatment dose can be delivered by all of the interstitialtreatment fibers simultaneously to the entire target region or deliveredsequentially (incremental treatment dose) in time by smaller sub-groupsof the fibers to portions of the target region. Preferably, anincremental treatment dose to a portion of the target region from asub-group of one or more interstitial treatment fibers (that is part ofthe larger total number of interstitial treatment fibers) is included inthe treatment dose only when the fluence rate to the portion of thetarget region from the sub-group is equal to or greater than a thresholdfluence rate. Whether the threshold treatment dose is deliveredsimultaneously to the entire target region or delivered sequentially intime to portions of the target region, at the end of the treatment everyelementary volume of the target region should preferably receive atleast a threshold treatment dose at a threshold fluence rate or higher.

At 120, the computer processor receives an initial oxygen concentrationfor the target region and an initial oxygen flow rate into the targetregion. The initial oxygen concentration and the initial oxygen flowrate can be determined by measurements taken on the target region of thepatient. Oxygen concentration can be measured with, for example but notlimited to, an OxyLite Pro oxygen monitor (Oxford Optronix, Oxford, UK)and blood flow rate (proportional to oxygen flow rate) can bedetermined, for example, by diffuse correlation spectroscopy. For bothtypes of measurements, see Ong et. al.; Reactive oxygen species explicitdosimetry for Photofrin-mediated pleural photodynamic therapy, PhotochemPhotobiol. 2020; 96: 340-348. If measurement results are not available,data from published or unpublished results may be substituted.

At 125, the computer processor receives initial tissue opticalproperties for the target region. Tissue optical properties can bedetermined by measurements taken on the target region of the patient.The tissue optical properties comprise the light absorption parameter,mua (or μ_(a)) the light scattering parameter, mus (or μ_(s)), thescattering anisotropy factor, g_(s), and the index of refraction, n.Note that the scattering anisotropy factor, g_(s), is a differentparameter than the photokinetic parameter, g, for the oxygen intakerate. The optical properties μ_(a) and μ_(s) may be measured, forexample, by broadband reflectance spectroscopy (Finlay et. al., Diffusereflectance spectra measured in vivo in human tissues duringPhotofrin-mediated pleural photodynamic therapy, Proc SPIE Int Soc OptEng. 2006, 6139). If measurement results are not available, data frompublished or unpublished results may be substituted. The tissue opticalproperties used in simulations of the threshold treatment dose may bedifferent for each material (e.g. target region, healthy tissue, air).

At 130, one or more locations in the target region for inserting one ormore interstitial treatment fibers to deliver the treatment light aredetermined, either manually or by the computer processor. Preferably theinterstitial treatment fibers are surrounded by light-transparentcatheters. Light-transparent catheters are commercially available fromvendors such as, for example, Best Medical International, Inc.,Springfield, Va. The interstitial treatment fibers may be non-diffusingoptical fibers or preferably, diffusing optical fibers. Diffusingoptical fibers can be obtained from vendors such as, for example,Medlight S.A., Switzerland. Standard diffuser lengths are 10, 15, 20,25, 30, 40, 50, 70 mm.

Manual means for determining locations of interstitial treatment fibersinclude letting the treating clinician decide on the positions of theinterstitial treatment fibers. This may be required if there aretreatment-sensitive organs-at-risk near the target region. In any case,the treating clinician makes the final decision on the position of theinterstitial treatment fibers. Another option for determining locationsof interstitial treatment fibers is to use a standard brachytherapytransperineal implant template, which has a rectangular array of holeswith 5 mm center-to-center separation that can be used to positionlight-transmitting catheters and interstitial treatment fibers in aregular or non-regular array. Once the positions of the one or moreinterstitial treatment fibers have been determined, one can use anygeometry processing software to create cylindrical holes into thecomputer-generated 3D shape of the target region where the interstitialtreatment fibers will be located.

At 135, a plurality of computational spatial elements for the targetregion and for the location(s) of the emitting surface(s) of at leastone interstitial treatment fiber are determined. Simulations of thetreatment light dose and fluence rate can be done by Monte Carlo (MC)methods or Finite Element (FE) methods. Voxel elements or tetrahedralmesh elements can be used as the computational spatial elements for MCsimulation. Tetrahedral mesh elements can be chosen as computationalspatial elements for FE numerical calculations.

At 140, the three initial variables for the treatment plan parametersare specified: therapeutic light power, light emitting length andtherapeutic light treatment time, for each at least one interstitialtreatment fiber. This can be done by manual means or by automatic orsemi-automatic optimization means. Therapeutic light power is the totallight power directed into the entire light emitting length of theinterstitial treatment fiber and is expressed, for example, in units ofmilliwatts (mW). Alternatively, in many I-PDT publications, therapeuticlight power is defined as light power per unit length of the entirelight emitting length expressed, for example, in milliwatts percentimeter (mW/cm) of light emitting length.

At 145, the fluence rates to each of the plurality of computationalspatial elements for delivering the treatment light are determined. Thisis done prior to using the photokinetic rate equations and thephotosensitizer photokinetic rate parameters to calculate the treatmentdose. The calculations can be done using either MC or FE methods.

At 150, the treatment dose to the interior volume of the target regionis determined. The fluence rates calculated at 145 for each of theplurality of computational spatial elements as well as the photokineticrate equations and the photosensitizer photokinetic rate parameters areused for determining the treatment dose to the interior volume of thetarget region. Additionally or optionally, the treatment dose to theboundary of the target region for each of the plurality of computationalspatial elements may also be determined at 150.

At 155, it is determined whether the treatment dose is greater thanthreshold treatment dose. Note that the threshold treatment dose isdefined at 115. Preferably the threshold treatment dose is a thresholdPDT-dose or a threshold [ROS]_(dose). The threshold [ROS]_(dose) may bea threshold [¹O₂]_(dose). It is more preferable that each treatmentutilizing a primary threshold PDT-dose or primary threshold [ROS]_(dose)optionally adds a secondary dose metric, where the secondary dose metricis a threshold fluence rate ϕ needed in order to kill cancer cells orwhere the secondary dose metric is a threshold light dose. For effectivetreatment, it is preferred that the treatment dose is greater than thethreshold treatment dose for at least 80 percent of the computationalspatial elements of the interior volume of the target region andoptionally for at least 80 percent of the computational spatial elementsof the boundary of the target region. More preferably the treatment doseis greater than the threshold treatment dose for at least 90 percent ofthe computational spatial elements of the interior volume of the targetregion and optionally for at least 90 percent of the computationalspatial elements of the boundary of the target region. Most preferablythe treatment dose is greater than the threshold treatment dose for allor substantial all of the computational spatial elements of the interiorvolume of the target region and optionally for all or substantially allof the computational spatial elements of the boundary of the targetregion.

If the answer is ‘No’, at 160, the three variables (therapeutic lightpower, light emitting length and therapeutic light treatment time) foreach at least one interstitial treatment fiber are updated and themethod 100 returns to 140. 140, 145, 150 and 155 are then repeated untilthe treatment dose is greater than the threshold treatment dose in thepreferred percent of the target region. Note that increasing thetherapeutic light power increases the fluence rate.

If the answer is ‘Yes’, at 165, the simulation is terminated.

Optimization means for Steps 140 to 165 may be done by optimizationsoftware that may include, but is not limited to, Cimmino's method asdisclosed in U.S. Pat. No. 8,986,358 and convex optimization (Yassine etal., “Automatic interstitial photodynamic therapy planning via convexoptimization,” Biomedical Optics Express, Vol. 9, No. 2 (1 Feb. 2018)).

Additional features can be added to the method 100 as illustrated inFIG. 2 . The steps described in FIG. 2 are usually done after the shapeof the target region has been obtained by means including, but notlimited to, a computed tomography (CT) scan, a positron emissiontomography (PET) scan, a magnetic resonance imaging (MRI) scan, anultrasound image or a 3D camera image, but before a clinician beginstreatment.

Once a clinician inserts interstitial treatment fibers into the targetregion, the clinician may find that the locations of the interstitialtreatment fibers are different than in the initial treatment plan. Theinterstitial photodynamic therapy treatment plan parameters should beupdated to take into account the change(s) in the location(s) of the atleast one interstitial treatment fiber for the target region that haveoccurred since the interstitial photodynamic therapy treatment plan wasfirst generated. In addition, the interstitial photodynamic therapytreatment plan may need to be updated before or during the treatment ifthere are measurements showing changes for the target region in at leastone of the initial photosensitizer concentration, the plurality ofinitial photosensitizer photokinetic rate parameters, the initial tissueoxygen concentration, the initial tissue optical properties or theinitial oxygen flow rate.

FIG. 3 illustrates an alternative embodiment of the present disclosure.Method 170 illustrated in FIG. 3 includes the method illustrated in FIG.2 and additional steps required for updating the locations of theinterstitial fibers and/or for updating parameters including, but notlimited to, the initial PS concentration, the initial PS photokineticrate parameters, the initial oxygen concentration, the initial oxygenflow rate and the initial tissue optical parameters.

Method 170 includes 105, 110, 115, 120, 125, 130, 135, 140, 145 and 150as in the method 100.

Further, as in the method 100, in method 170, at 155, it is determinedwhether the treatment dose greater than threshold treatment dose.Preferably the threshold treatment dose is a threshold PDT-dose or athreshold [ROS]_(dose). The threshold [ROS]_(dose) may be a threshold[¹O₂]_(dose). It is more preferable that each treatment utilizing aprimary threshold PDT-dose or primary threshold [ROS]_(dose) optionallyadds a secondary dose metric, where the secondary dose metric is athreshold fluence rate ϕ needed in order to kill cancer cells or wherethe secondary dose metric is a threshold light dose. Preferably method170 determines that the treatment dose is greater than the thresholdtreatment dose for at least 80 percent of the computational spatialelements of the interior volume of the target region and optionally forat least 80 percent of the computational spatial elements of theboundary of the target region. More preferably method 170 determinesthat the treatment dose is greater than the threshold treatment dose forat least 90 percent of the computational spatial elements of theinterior volume of the target region and optionally for at least 90percent of the computational spatial elements of the boundary of thetarget region. Most preferably method 170 determines that the treatmentdose is greater than the threshold treatment dose for all orsubstantially all of the computational spatial elements of the interiorvolume of the target region and optionally for all or substantially allof the computational spatial elements of the boundary of the targetregion.

If the answer is ‘No’, at 160 of method 170, the three variables(therapeutic light power, light emitting length and therapeutic lighttreatment time) for each at least one interstitial treatment fiber areupdated. The method 170 then returns to 140 and repeats 140, 145, 150and 155 until the treatment dose is greater than the threshold treatmentdose in the preferred percent of the target region.

If the answer at 155 of the method 170 is ‘Yes’, the method 170 proceedsto 175, where it is determined whether the initial treatment planlocation(s) of the interstitial treatment fibers have changed. If theanswer is ‘Yes’, at, 180, the locations are updated. The method 170 thenreturns to 130 and repeats 130 to 175. If the answer is “No’, method 170proceeds to 185.

At 185 of the method 170 it is determined whether the initial treatmentplan PS, oxygen or optical parameters have changed. If the answer is‘Yes’, at 190, the parameters are updated. The new parameters arereturned to 110, 120, 125, and 110 to 185 are repeated. If the answer is“No’, the method 170 proceeds to 195, which terminates the simulation.

Other additional features may comprise methods that include a displaymeans to enable a user to visualize a two-dimensional or athree-dimensional image of the treatment dose and/or a two-dimensionalor a three-dimensional image of under- and over-doses and/or visualizefluence rates. In addition, the display means may also enable the userto visualize a two-dimensional or a three-dimensional image of thetreatment dose and/or a two-dimensional or a three-dimensional image ofunder- and over-doses overlaid onto, respectively, a two-dimensional ora three-dimensional image of the shape information for the targetregion.

Furthermore, a method 100 or a method 170 of the present disclosure mayinclude situations wherein the threshold treatment dose is a thresholdlight dose delivered at least at a threshold fluence rate.

In another aspect the present disclosure provides, systems forgenerating an interstitial photodynamic therapy treatment plans.Advantageously, the systems disclosed herein establish a treatment planthat will deliver at least a threshold treatment dose over the entiretarget region and that is also within an acceptable tolerance that willnot significantly damage healthy tissue and organs-at-risk. Thethreshold treatment dose can be a threshold PDT-dose, a threshold[ROS]_(dose) or a threshold light dose. Preferably the thresholdtreatment dose is a threshold PDT-dose or a threshold [ROS]_(dose). Thethreshold [ROS]_(dose) may be a threshold [¹O₂]_(dose). It is morepreferable that each treatment utilizing a primary threshold PDT-dose orprimary threshold [ROS]_(dose) optionally adds a secondary dose metric,where the secondary dose metric is a threshold fluence rate ϕ needed inorder to kill cancer cells or where the secondary dose metric is athreshold light dose.

FIG. 6 schematically depicts a system for treatment planning 600 foroptimizing light dose delivery to a target region in accordance with anembodiment of the present disclosure. The system comprises a computerprocessor 605 which is configured to receive input information for thetreatment plan and to determine a treatment dose for a target region ina patient.

In some embodiments, the system 600 includes a computer processor 605configured to perform the method 100 illustrated in FIG. 2 or the method170 illustrated in FIG. 3 . For example, as depicted in FIG. 4 , at 202,the computer processor 605 receives the information to perform themethod 100. Similarly, FIG. 5 depicts the computer processor 605performing the method 170 illustrated in FIG. 3 . Computer processor 605may comprise a multi-core processor and/or may comprise a plurality ofcomputer processors. Computer processor 605 may further comprise one ormore graphical processing units (GPUs) to reduce computing times.

The system 600 may further include inputs and outputs to the computerprocessor 605. The inputs to the computer processor 605 may include, butare not limited to, the target region shape 610, the initialphotosensitizer concentration 615 in the target region, the initialphotosensitizer rate parameters 620, the desired threshold treatmentdose 625, the initial tissue oxygen concentration 630 in the targetregion, the initial tissue oxygen flow rate 635 into the target regionand the initial tissue optical properties 640 in the target region.While not explicitly shown in FIG. 6 , the system 600 may furtherinclude apparatus, such as various types of sensors, for obtaining theinputs 610, 615, 620, 625, 630, 635, and 640.

The outputs from the computer processor 605 include, but are not limitedto, a determination of the interstitial treatment fiber locations 645, adetermination of the treatment plan 650 and a display means 655 forvisualization of, for example, the calculated treatment doses for allportions of the target region. The outputs 645 and 650 may be the resultof performance of the method 100 or the method 170 by the computerprocessor 605.

While not explicitly shown, system 600 may further include apparatus forproviding the treatment dose to the target region. The apparatus mayinclude at least one power source, at least one light source, at leastone interstitial treatment fiber, and at least one optical fiber totransmit light from the at least one light source to the at least oneinterstitial treatment fiber. The light source may include one or morelight emitting diodes, one or more lasers, or a combination thereof. Thewavelength of the light source is not particularly limited, but isdictated by the particular photosensitizer being used. Preferably, theat least one interstitial treatment fiber is a light diffusinginterstitial treatment fiber.

As depicted in FIG. 4 , the computer processor 605 performs the method100 as follows. At step 202, the computer processor receives theinformation needed to perform the subsequent steps. For example, thecomputer processor may receive inputs depicted in FIG. 6 as 610, 615,620, 625, 630, 635, and 640, in some embodiments. These received inputsare depicted in FIG. 4 as 205, 210, 215, 220 and 225.

The computer processor is configured to perform, at 205, wherein thecomputer processor receives information relating to the target region.The information relating to the target region may include, for example,the shape of the target region, the size of the target region, and/orthe geometric coordinates of various portions of the target region. Theinformation relating to the target region may be received from, forexample, a computed tomography (CT) scan, a positron emission tomography(PET) scan, a magnetic resonance imaging (MRI) scan, an ultrasound imageor a 3D camera image. CT scans and MRI scans, for example, provide insome embodiments, the raw data relating to the target region may beprocessed to obtain a 2-dimensional (2D) slice information about a3-dimensional (3D) target region. The raw data may be processed usingcommercially-available or open-source geometry processing softwarepackages. A 3D image of the target may then be constructed using theslice information, manually or automatically by outlining the targetregion in each slice, and using the outline to then construct a 3D imageof the target region.

The computer processor may be further configured to perform, at 210,wherein the computer processor receives initial photosensitizer (PS)concentration and initial photosensitizer photokinetic rate parameters.The photosensitizer photokinetic rate parameters will be different fordifferent photosensitizers. A table of photokinetic rate parameters fora variety of photosensitizers can be found in Kim et. al.; “On the invivo photochemical rate parameters for PDT reactive oxygen speciesmodeling,” Phys. Med. Biol. 62 (2017) R1-R48.

The computer processor may be further configured to perform, at 215,wherein the computer processor receives threshold treatment doseinformation for the target region. Preferably the primary thresholdtreatment dose is a PDT-dose or a threshold [ROS]_(dose). The threshold[ROS]_(dose) may be a threshold [¹O₂]_(dose). The threshold PDT-dose orthe threshold [ROS]_(dose) may be obtained from prior clinical data orfrom published or unpublished results. It is more preferable that eachtreatment utilizing a primary threshold PDT-dose or primary threshold[ROS]_(dose) optionally add a secondary dose metric, where the secondarydose metric is a threshold fluence rate ϕ needed in order to kill cancercells or where the secondary dose metric is a threshold light dose.

The threshold treatment dose can be delivered by all of the interstitialtreatment fibers simultaneously to the entire target region or deliveredsequentially in time by smaller sub-groups of the fibers to portions ofthe target region. Preferably an incremental treatment dose to a portionof the target region from a sub-group of one or more interstitialtreatment fibers (that is part of the larger total number ofinterstitial treatment fibers) is included in the treatment dose onlywhen the fluence rate to the portion of the target region from thesub-group is equal to or greater than a threshold fluence rate.

The computer processor may be further configured to perform, at 220,wherein the computer processor receives an initial oxygen concentrationfor the target region and an initial oxygen flow rate into the targetregion. The initial oxygen concentration and the initial oxygen flowrate can be determined by measurements taken on the target region of thepatient. If measurement results are not available, data from publishedor unpublished results may be substituted.

The computer processor may be further configured to perform, at 225,wherein the computer processor receives receive initial tissue opticalproperties for the target region. Tissue optical properties can bedetermined by measurements taken on the target region of the patient. Ifmeasurement results are not available, data from published orunpublished results may be substituted. The tissue optical propertiescomprise the light absorption parameter, mua (or μ_(a)), the lightscattering parameter, mus (or μ_(s)), the scattering anisotropy factor,g_(s), and the index of refraction, n. Note that the scatteringanisotropy factor, g_(s), is a different parameter than the photokineticparameter, g, for the oxygen intake rate. The tissue optical propertiesused in simulations of the threshold treatment dose may be different foreach material (e.g. target region, healthy tissue, air).

The computer processor may be further configured to perform, at 230,wherein the computer processor determines, by manual input means or byactions of the processor, location(s) in the target region for insertingat least one interstitial treatment fiber to deliver the treatmentlight. Preferably the interstitial treatment fibers are surrounded bylight-transmitting catheters. Light-transmitting catheters can beobtained commercially from vendors such as, for example, Best MedicalInternational, Inc., Springfield, Va. The interstitial treatment fibersmay be non-diffusing optical fibers or, preferably, each interstitialtreatment fiber has a distal end that is a light diffusing interstitialoptical fiber. Light diffusing interstitial optical fibers can beobtained from Medlight S.A., Switzerland. Standard diffuser lengths are10, 15, 20, 25, 30, 40, 50, 70 mm. Manual means for determininglocations of interstitial treatment fibers include letting the treatingclinician decide on the positions of the interstitial treatment fibers.This may be required if there are treatment-sensitive organs-at-risknear the target region. In any case, the treating clinician makes thefinal decision on the positions of the interstitial treatment fibers.Another option for determining locations of interstitial treatmentfibers is to use a standard brachytherapy transperineal implanttemplate, which has a rectangular array of holes with 5 mmcenter-to-center separation that can be used to positionlight-transmitting catheters and interstitial treatment fibers in aregular or non-regular array. Once the positions of the one or moreinterstitial treatment fibers have been determined, one can use ageometry processing software package to create cylindrical holes intothe computer-simulated 3D shape of the target region where theinterstitial treatment fibers will be located.

The computer processor may be further configured to perform, at 235,wherein the computer processor determines a plurality of computationalspatial elements for the target region and for the location(s) of theemitting surface(s) of at least one interstitial treatment fiber.Simulations of the treatment light dose can be done by Monte Carlo (MC)methods or Finite Element (FE) methods. Voxel elements or tetrahedralmesh elements can be used as the computational spatial elements for MCsimulation. Tetrahedral mesh elements can be chosen as computationalspatial elements for FE numerical calculations.

The computer processor may be further configured to perform, at 240,wherein the computer processor specifies initial values for thevariables comprising therapeutic light power, light emitting length andtherapeutic light treatment time for each at least one interstitialtreatment fiber. This can be done by manual means or by automatic orsemi-automatic optimization means.

The computer processor may be further configured to perform, at 245,wherein the computer processor determines the fluence rates to each ofthe plurality of computational spatial elements for delivering thetreatment light. This step is preferably performed prior to using thephotokinetic rate equations and the photosensitizer photokinetic rateparameters to calculate the treatment dose. The calculations can beperformed using either MC or FE software, or any other suitable method.

The computer processor may be further configured to perform, at 250,wherein the computer processor determines the treatment dose to theinterior volume and the boundary of the target region for each of theplurality of computational spatial elements. The determination of thetreatment dose is performed using the fluence rates calculated at 245for each of the plurality of computational spatial elements, as well asthe photokinetic rate equations and the photosensitizer photokineticrate parameters.

The computer processor may be further configured to perform, at 255,wherein the computer processor determines whether the treatment dose isgreater than threshold treatment dose. The threshold treatment dose maybe the threshold treatment dose received at 215. At 255, the computerprocessor further determines the portion of the interior volume of thetarget region that has received a treatment dose greater than thethreshold treatment dose.

Preferably the threshold treatment dose is a threshold PDT-dose or athreshold [ROS]_(dose). The threshold [ROS]_(dose) may be a threshold[¹O₂]_(dose). It is more preferable that each treatment utilizing aprimary threshold PDT-dose or primary threshold [ROS]_(dose) optionallyadds a secondary dose metric, where the secondary dose metric is athreshold fluence rate ϕ needed in order to kill cancer cells or wherethe secondary dose metric is a threshold light dose. For effectivetreatment, it is preferred that the treatment dose is greater than thethreshold treatment dose for at least 80 percent of the computationalspatial elements of the interior volume of the target region andoptionally for at least 80 percent of the computational spatial elementsof the boundary of the target region. More preferably the treatment doseis greater than the threshold treatment dose for at least 90 percent ofthe computational spatial elements of the interior volume of the targetregion and optionally for at least 90 percent of the computationalspatial elements of the boundary of the target region. Most preferablythe treatment dose is greater than the threshold treatment dose for allor substantially all of the computational spatial elements of theinterior volume of the target region and optionally for all orsubstantially all of the computational spatial elements of the boundaryof the target region.

The computer processor may be further configured to perform, at 260,wherein the computer processor, in response to a determination that atleast a predetermined portion of the target region did not receive atreatment dose greater than the threshold treatment dose, updates one ormore of variables including therapeutic light power, light emittinglength and therapeutic light treatment time for each at least oneinterstitial treatment fiber, returns to 240, and repeats correspondingof 240, 245, 250 and 255 until the treatment dose for at least thepredetermined portion of the target region is greater than the thresholdtreatment dose. Note that increasing the therapeutic light powerincreases the fluence rate.

On the other hand, the computer processor of the system 200 may beconfigured to perform a step 265, wherein the computer processor, inresponse to a determination that at least a predetermined portion of thetarget region received a treatment dose greater than the thresholdtreatment dose, terminates the simulation.

At 240, 245, 250, 255, 260 and 265, where needed, optimization ofcorresponding parameters can be performed using software programs such,for example, one disclosed in U.S. Pat. No. 8,986,358 or convexoptimization disclosed in Yassine et al., “Automatic interstitialphotodynamic therapy planning via convex optimization,” BiomedicalOptics Express, Vol. 9, No. 2 (1 Feb. 2018). Optionally for a system ofthis invention, the computer processor is configured to calculate atreatment dose wherein the treatment dose is a light dose delivered atleast at a threshold fluence rate.

In an example of a system that can be utilized for generating aninterstitial photodynamic therapy treatment plan, the system maycalculate, for example, the fluence rate, PDT-dose, [ROS]_(dose),[¹O₂]_(dose) and light dose for each of the plurality of computationalspatial elements for interstitial photodynamic therapy. The system maycombine, in one integrated device, FE or MC simulations of lighttransport, fluence rate and light dose (fluence) as well asphotokinetics (PK) simulations of [ROS]_(dose), [¹O₂]_(dose), andPDT-dose. The system may perform fluence rate simulations for each ofthe plurality of computational spatial elements using the light power ofthe interstitial treatment fibers and the tissue optical properties ofthe target region as inputs. The PK simulations may use the fluence rateresults plus inputs of PS concentration, PS photokinetics parameters,tissue oxygen concentration and oxygen flow rates to calculate[ROS]_(dose), [¹O₂]_(dose), and PDT-dose. The calculated PDTphotokinetics may include light-PS-excitation, the PS-to-oxygenexcitation to generate singlet oxygen, the singlet oxygen reaction withthe target region and the singlet oxygen reaction with the PS (resultingin photobleaching). In some embodiments, graphics on the system maydisplay 2D and 3D outputs of light fluence (light dose), fluence rate,PDT-dose, [ROS]_(dose) and [¹O₂]_(dose) at every computational spatialelement in the 3D target. A clinician can use this information tolocalize areas of under-treatment and make corrections to the treatmentplan.

In some embodiments, the computer processor 605 of the system 600 can befurther configured to perform additional steps as illustrated in FIG. 5. The steps illustrated in FIG. 4 are performed after the shape of thetarget region has been obtained using, for example, a computedtomography (CT) scan, a positron emission tomography (PET) scan, amagnetic resonance imaging (MRI) scan, an ultrasound image or a 3Dcamera image, but before a clinician begins treatment.

Once the clinician inserts interstitial treatment fibers into the targetregion, however, the clinician may find that the locations of theinterstitial treatment fibers are different than in the initialtreatment plan. The initial interstitial photodynamic therapy treatmentplan parameters should be updated to take into account the change(s) inthe location(s) of the at least one interstitial treatment fiber for thetarget region that have occurred since the interstitial photodynamictherapy treatment plan was first generated. In addition, theinterstitial photodynamic therapy treatment plan may need to be updatedbefore or during the treatment if there are measurements showing changesin parameters for the target region in at least one of the initialphotosensitizer concentration, the plurality of initial photosensitizerphotokinetic rate parameters, the initial tissue oxygen concentration,the initial tissue optical properties or the initial oxygen flow rate.

As depicted in FIG. 5 , the computer processor 605 performs the method170 depicted in FIG. 3 by performing the operations as depicted in FIG.4 and the additional operations, illustrated in FIG. 5 , for updatingthe locations of the interstitial fibers and/or for updating parametersincluding, but not limited to, the initial PS concentration, the initialPS photokinetic rate parameters, the initial oxygen concentration, theinitial oxygen flow rate and the initial tissue optical parameters.

Operations at 202 to 250 in in FIG. 5 are identical to those at 202 to250 in FIG. 4 . However, when performing the method 170, as shown inFIG. 5 , the computer processor may be configured to perform 255,wherein the computer processor determines whether the treatment dose isgreater than threshold treatment dose, that is received at 215.Preferably the threshold treatment dose is a threshold PDT-dose or athreshold [ROS]_(dose). The threshold [ROS]_(dose) may be a threshold[¹O₂]_(dose). It is more preferable that each treatment utilizing aprimary threshold PDT-dose or primary threshold [ROS]_(dose) optionallyadds a secondary dose metric, where the secondary dose metric is athreshold fluence rate ϕ needed in order to kill cancer cells or wherethe secondary dose metric is a threshold light dose. The computerprocessor of system 270, at 255, further determines the portion of theinterior volume of the target region that has received a treatment dosegreater than the threshold treatment dose.

For effective treatment, it is preferred that the treatment dose isgreater than the threshold treatment dose for at least 80 percent of thecomputational spatial elements of the interior volume of the targetregion and optionally for at least 80 percent of the computationalspatial elements of the boundary of the target region. More preferablythe treatment dose is greater than the threshold treatment dose for atleast 90 percent of the computational spatial elements of the interiorvolume of the target region and optionally for at least 90 percent ofthe computational spatial elements of the boundary of the target region.Most preferably the treatment dose is greater than the thresholdtreatment dose for all or substantially all of the computational spatialelements of the interior volume of the target region and optionally forall or substantially all of the computational spatial elements of theboundary of the target region.

Referring back to FIG. 5 , the computer processor may be furtherconfigured to perform 260, wherein the computer processor, in responseto a determination that at least a predetermined portion of the targetregion did not receive a treatment dose greater than the thresholdtreatment dose, updates one or more of variables including therapeuticlight power, light emitting length and therapeutic light treatment timefor each at least one interstitial treatment fiber, returns to 240, andrepeats corresponding of 240, 245, 250 and 255 until the treatment dosefor at least the predetermined portion of the target region is greaterthan the threshold treatment dose. Note that increasing the therapeuticlight power increases the fluence rate.

On the other hand, if it is determined that at least a predeterminedportion of the target region has received a treatment dose greater thanthe threshold treatment dose, at 275, the computer processor maydetermine whether initial treatment plan location(s) of the interstitialtreatment fibers has changed. The computer processor, in response to adetermination that initial treatment plan location(s) of theinterstitial treatment fibers has changed, at 280, may update thelocation(s) of the interstitial treatment fibers by manual means or byactions of the processor, then returns to 230 and repeats 230 to 275.Manual means for determining locations of interstitial treatment fibersinclude letting the treating clinician decide on the positions of theinterstitial treatment fibers. In any case, the treating clinician makesthe final decision on the positions of the interstitial treatmentfibers. However, if it is determined that the initial treatment planlocation(s) of interstitial treatment has not changed, the computerprocessor proceeds to 285.

The computer processor may be further configured to determine, at 285,whether any of initial treatment plan PS, oxygen or optical parametershave changed. In response to a determination that at least one of PS,oxygen or optical parameters have changed, at 290, the computerprocessor updates the changed parameters, returns the new parameters tocorresponding of the 210, 220, 225, and repeats 210 to 285. On the otherhand, if the initial treatment plan parameters are determined not tohave changed, the computer processor proceeds to 295, which ends thesimulation.

In some embodiments, the system 600 for generating an interstitialphotodynamic therapy treatment plan may further include one or moreadditional components. For example, in some embodiments, the system 600may include at least one therapeutic treatment light source such as, forexample, a laser or light-emitting diode.

In some embodiments, the system may include at least one interstitialtreatment fiber functionally coupled to the at least one therapeutictreatment light source for delivering deliver the treatment light to thetarget region. In such embodiments, a distal end of least oneinterstitial treatment fiber is preferably a light diffusinginterstitial treatment fiber.

In some embodiments, the system includes a diagnostic light sourcefunctionally coupled to an interstitial diagnostic fiber. In someembodiments, the diagnostic light source may be the same as thetreatment light source. In such embodiments, the system additionallyincludes optics for bifurcating the light from the treatment lightsource into a second light source that functions as the diagnostic lightsource. In some embodiments, the diagnostic light source is separatefrom the treatment light source. In such embodiments, the diagnosticlight source and the treatment light source may or may not be poweredusing a same power source.

In some embodiments, the system includes at least one interstitialdetector to detect diagnostic light generated by the diagnostic lightsource and/or treatment light generated by the therapeutic treatmentlight source and/or photosensitizer fluorescence generated by thediagnostic light source or the treatment light source. The detector mayinclude, for example, one or more photodiodes.

In some embodiments, the system includes at least one spectrophotometerfunctionally coupled to the at least one interstitial detector to detectthe treatment light intensity and/or the diagnostic light intensityand/or the fluorescence light intensity generated by the therapeutictreatment light source or the diagnostic light source.

In some embodiments, the system includes one or more light-transmittingcatheters enclosing the at least one therapeutic interstitial treatmentfiber, the at least one interstitial diagnostic fiber and the at leastone interstitial detector.

In some embodiments, the system includes a display to enable a user tovisualize a two-dimensional or three-dimensional image of the treatmentdose and/or a two-dimensional or three-dimensional image of under- andover-doses and/or visualize fluence rates. In addition, the displaymeans may also enable the user to visualize a two-dimensional orthree-dimensional image of the treatment dose and/or a two-dimensionalor three-dimensional image of under- and over-doses overlaid onto,respectively, a two-dimensional and/or three-dimensional image of theshape information for the target region.

FIG. 7 illustrates another example of a system 700 for treatmentplanning that includes the means for delivering and monitoring thetreatment plan in a target region. For illustrative purposes, system 700in FIG. 7 is greatly simplified to include only one light diffusinginterstitial optical fiber 720 for providing treatment light to thetarget region 702, one interstitial detector 760 for diagnosticmonitoring and, optionally, one light diffusing interstitial opticalfiber 740 for delivering diagnostic light for diagnostic monitoring. Incontrast to this simplified system, a typical treatment planning systemused in the clinic that includes means for delivering and monitoring thetreatment plan may have a plurality of light diffusing interstitialoptical fibers 720 for delivering treatment light to the target region702, a plurality of interstitial detectors 760 for diagnosticmonitoring, and, optionally, a plurality of light diffusing interstitialoptical fibers for delivering diagnostic light for diagnosticmonitoring.

System 700 in FIG. 7 comprises a computer processor 705, which acts as acontroller for system 700. Computer processor 705 may optionally besubstantially the same computer processor as utilized in system 600. Thecomputer processor 705 may optionally be configured to perform themethod 100 or the method 170. In some embodiments, computer processor705 can control the therapeutic treatment light source 710 anddiagnostic light source 730 as well as receive information fromspectrometer 750.

Therapeutic treatment light source 710 may be any light source thatemits light of the proper wavelength (or wavelength range) to beabsorbed by the PS that has previously been injected or otherwisetransported to target region 702. Example therapeutic treatment lightsources 710 include, but are not limited to, continuous wave (CW)lasers, pulsed lasers, fiber optic lasers, light emitting diodes (LEDs),fluorescent light sources (wavelength filtered or unfiltered), orincandescent light sources (wavelength filtered or unfiltered).Preferred therapeutic treatment light sources 710 are CW lasers, fiberoptic lasers and LEDs.

Light from the therapeutic treatment light source 710 is preferablytransmitted to the target region 702 by an interstitial treatment fiber715. Preferably the distal end of the interstitial treatment fiber 715is a light-diffusing interstitial treatment fiber 720. Light-diffusinginterstitial optical fibers can be obtained from, for example, MedlightS.A., Switzerland. Standard diffuser lengths are 10, 15, 20, 25, 30, 40,50, 70 mm. However, other lengths are contemplated within the scope ofthe present disclosure.

Diagnostic light source 730 may be any light source that emits light ofthe proper wavelength to monitor the I-PDT. The monitoring light couldhave the same wavelength (or wavelength range) as the therapeutictreatment light source or the wavelength could be different. One canmonitor the I-PDT at the same wavelength as the therapeutic lightsource, but at a lower intensity, to monitor any changes in the opticalproperties of the target region. Changes in the optical properties canoccur, for example, when oxygen is depleted from the target region as aresult of the I-PDT. An example of a wavelength that is different fromthe therapeutic treatment light is any wavelength that can excitefluorescence of the PS. Monitoring the fluorescence emission of the PSallows for monitoring changes in the concentration of the PS due tophotobleaching resulting from the I-PDT. Without wishing to be bound bytheory, changes in the PS concentration may affect the resultingPDT-dose or the resulting reactive oxygen species dose. Examplediagnostic light sources 730 include, but are not limited to, continuouswave (CW) lasers, pulsed lasers, fiber optic lasers, light emittingdiodes (LEDs), fluorescent light sources (wavelength filtered orunfiltered), or incandescent light sources (wavelength filtered orunfiltered). Preferred diagnostic light sources 730 are CW lasers, fiberoptic lasers and LEDs.

Light from the diagnostic light source 730 is preferably transmitted tothe target region 702 by an interstitial diagnostic fiber 735.Preferably the distal end of the interstitial diagnostic fiber 735 is alight-diffusing interstitial diagnostic fiber 740.

The I-PDT process can be monitored using an interstitial detector 760functionally coupled to spectrometer 750 via an interstitial opticalfiber 755. The interstitial detector 760 can measure the intensity oftreatment light coming from the light-diffusing interstitial treatmentfiber 720 or the intensity of diagnostic light coming from thelight-diffusing interstitial diagnostic fiber 740 or fluorescenceemission from the PS that is excited by the light-diffusing interstitialdiagnostic fiber 740 or excited by the light-diffusing interstitialtreatment fiber 720. Interstitial detectors are available from, forexample, Medlight S.A., Switzerland.

Light-diffusing interstitial optical fiber 720, interstitial detector760 and light-diffusing interstitial diagnostic fiber 740 are preferablyenclosed in hollow, light-transmitting catheters 770. Light-transmittingcatheters 770 can be obtained from, for example, Best MedicalInternational, Inc., Springfield, Va.

System 700 optionally includes a display 790 for visualizing thetreatment plan and for monitoring the progress of the treatment. Forexample, the display can enable a user to visualize a two-dimensional orthree-dimensional image of the treatment dose and/or a two-dimensionalor three-dimensional image of under- and over-doses and/or visualizefluence rates. In addition, the display means may also enable the userto visualize a two-dimensional or a three-dimensional image of under-and over-doses overlaid onto, respectively, a two-dimensional orthree-dimensional image of the shape information for the target region.

In some embodiments, the system 700, or parts thereof can be executedusing a mobile device such as, for example, a mobile phone or a tabletcomputer. For example, the computer processor 705 and the display 790may be those of a mobile phone or a tablet computer, while a data buscan connect the treatment light source, the diagnostic light source andthe spectrometer to the mobile phone or the tablet computer.

EXAMPLES Example 1: Generating a Tetrahedral Mesh for the Target Regionand One Interstitial Light Source

The shape 800 of an example target region is shown in FIG. 8 . Sliceinformation for the target region was obtained using magnetic resonanceimaging (MRI) scans. A 3D image processing software was used to processthe slice information, construct a 3D shape, and output the shape as aset of NURBS surfaces. FIG. 8 shows the resulting shape 800 as viewed ina geometry processing software viewer.

In general, the locations of one or more interstitial treatment fibersare determined by manual or automatic means. For illustrative purposesin this example, FIG. 9 shows the location of one interstitial treatmentfiber in target region 800. An open-source or a commercially availablegeometry processing software can be used to create the cylindrical hole810 into the computer-generated 3D shape of the target region 800 wherethe interstitial treatment fiber will be located.

A plurality of computational spatial elements for the target region andfor the location of the emitting surface for the one interstitialtreatment fiber were then determined. Computational spatial elements forFE methods were used, which are tetrahedral mesh elements. An initialtetrahedral mesh can be generated by an open-source or commerciallyavailable geometry processing software packages. This initial FE meshhas unlabeled mesh faces and nodes. FIG. 10 shows the target region1000, the cylindrical hole 1010 and the tetrahedral mesh 1020. Forsimplicity, only the surface triangular faces and nodes are shown (thenodes are located at the corner of the triangles). The surface of thecylindrical hole 1010 also is covered by the tetrahedral mesh 1030 asshown in an expanded view in FIG. 11 . The surface mesh 1030 defines theemitting surface for the interstitial treatment fiber. Later the meshfaces and nodes are labeled in order to do FE simulations.

Example 2: Determining Fluence Rates for the Target Region

The shape 1200 of an example target region is shown in FIG. 12 . Hole1210 is the location for an interstitial treatment fiber. In this casethe interstitial treatment fiber is a light-diffusing interstitial fiberthat has an emitting power of 200 mW/cm. Dosie™, a proprietary software,was used to estimate by the FE method the fluence rates for theplurality of computational spatial elements, where the computationalspatial elements are tetrahedral mesh elements. The tissue opticalparameters for the target region are the light absorption parametermua=0.05 mm⁻¹, the light scattering parameter mus=3.8 mm⁻¹, thescattering anisotropy factor, g_(s)=0.9, and the index of refraction,n=1.37. The results are shown in FIG. 12 and FIG. 13 . FIG. 12 shows thefluence rate values rendered over the outside surface of the targetvolume. FIG. 13 is a cross sectional view revealing the fluence ratevalues over the inside surface of the hole 1210. The graphical outputsare set to show the regions of the target area that receive a thresholdfluence rate of 8.4 mW/cm² (the threshold fluence rate shown in TABLE 4for mice). In the ‘lighter’ regions 1220, the fluence rate is equal toor greater than 8.4 mW/cm². In the ‘darker’ regions 1230 of the target,the fluence rate is less than 8.4 mW/cm², indicating that inserting atleast another light source fiber may be required to ensure that all thespatial elements receive the threshold fluence rate.

Example 3: Determine PDT-Dose for the Target Region

Using the calculated fluence rates for the tetrahedral mesh elementsfrom Example 2, one can use Dosie™ to calculate the PDT-dose for thetarget. The PS is Photofrin™. The simulation parameters for Photofrinare: β=11.9, δ=33, ξ=3.7E-03, σ=7.6E-05. The oxygen flow rate g=0.8μM/s, S_(Δ)=0.319, the oxygen concentration=83 μM and [PS]=4 μM. Thetreatment time is 2400 s (40 minutes). The results are shown in FIG. 14and FIG. 15 . FIG. 14 shows the outside surface 1400 of the target. FIG.15 is a cross sectional view showing the inside surface of the hole1410. The graphical outputs are set to show the regions of the targetarea that receive a threshold PDT-dose of 439 μM J/cm² (the thresholdPDT-dose shown in TABLE 2 for mice). In the ‘lighter’ regions 1420, thePDT-dose is equal to or greater than 439 μM J/cm². In the ‘darker’regions 1430 of the target, the PDT-dose is less than 439 μM J/cm²,indicating that at least another light source fiber may be required toensure that all the spatial elements receive the threshold PDT-dose.Preferably the threshold PDT-dose should be delivered at a fluence rategreater than a threshold fluence rate. Comparing FIG. 14 with FIG. 12and comparing FIG. 15 with FIG. 13 shows that the fluence rate isgreater than the threshold fluence rate of 8.4 mW/cm² in the areas wherethe PDT-dose is greater than the threshold PDT-dose of 439 μM J/cm².

Example 4: Determine [¹O₂]_(dose) for the Target Region

Using the calculated fluence rates for the tetrahedral mesh elementsfrom Example 2, one can use Dosie™ to calculate the [¹O₂]_(dose) for thetarget. The PS is Photofrin™. The simulation parameters for Photofrinare: β=11.9, δ=33, =3.7E-03, σ=7.6E-05. The oxygen flow rate g=0.8 μM/s,S_(Δ)=0.319, the oxygen concentration=83 μM and [PS]=4 μM. The treatmenttime is 2400 s (40 minutes). The results are shown in FIG. 16 and FIG.17 . FIG. 16 shows the outside surface 1600 of the target. FIG. 17 is across sectional view showing the inside surface of the hole 1610. Thegraphical outputs are set to show the regions of the target area thatreceive a threshold [¹O₂]_(dose) of 1 mM (approximately the threshold[¹O₂]_(dose) shown in TABLE 3 for mice). In the ‘lighter’ regions 1620,the [¹O₂]_(dose) is equal to or greater than 1 mM. In the ‘darker’regions 1630 of the target, the [¹O₂]_(dose) is less than 1 mM.Preferably the threshold [¹O₂]_(dose) should be delivered at a fluencerate greater than a threshold fluence rate. Comparing FIG. 16 with FIG.12 and comparing FIG. 17 with FIG. 13 shows that the fluence rate isgreater than the threshold fluence rate of 8.4 mW/cm² in the areas wherethe [¹O₂]_(dose) is greater than the threshold [¹O₂]_(dose) of 1 mM.

Examples 2, 3 and 4 show that one interstitial fiber may not sufficientto generate a threshold fluence rate, a threshold PDT-dose or athreshold [¹O₂]_(dose), respectively, over the entire target volume orboundary. Additional interstitial fibers may be needed for effectivetreatments.

While several exemplary aspects and embodiments have been discussedabove, those having skill in the art will recognize certainmodifications, permutations, additions and sub-combinations that arealso within the spirit and scope of this invention.

FURTHER CONSIDERATIONS

In some embodiments, any of the clauses herein may depend from any oneof the independent clauses or any one of the dependent clauses. In oneaspect, any of the clauses (e.g., dependent or independent clauses) maybe combined with any other one or more clauses (e.g., dependent orindependent clauses). In one aspect, a claim may include some or all ofthe words (e.g., steps, operations, means or components) recited in aclause, a sentence, a phrase or a paragraph. In one aspect, a claim mayinclude some or all of the words recited in one or more clauses,sentences, phrases or paragraphs. In one aspect, some of the words ineach of the clauses, sentences, phrases or paragraphs may be removed. Inone aspect, additional words or elements may be added to a clause, asentence, a phrase or a paragraph. In one aspect, the subject technologymay be implemented without utilizing some of the components, elements,functions or operations described herein. In one aspect, the subjecttechnology may be implemented utilizing additional components, elements,functions or operations.

The subject technology is illustrated, for example, according to variousaspects described below. Various examples of aspects of the subjecttechnology are described as numbered clauses (1, 2, 3, etc.) forconvenience. These are provided as examples and do not limit the subjecttechnology. It is noted that any of the dependent clauses may becombined in any combination, and placed into a respective independentclause, e.g., clause 1 or clause 5. The other clauses can be presentedin a similar manner.

Clause 1: A method of administering interstitial photodynamic therapy bydelivering treatment dose to a target region of a patient, the methodcomprising: receiving, at a processor, information associated with thetarget region, an initial photo-sensitizer concentration, a plurality ofinitial photosensitizer photokinetic rate parameters, and a thresholdtreatment dose for a photosensitizer, the threshold treatment dose beinga threshold photodynamic therapy-dose or a threshold reactive oxygenspecies dose; determining a location in the target region for insertingat least one interstitial treatment fiber to deliver the treatmentlight; determining, by the processor, initial values for therapeuticlight power, and light emitting length and therapeutic treatment timefor the at least one interstitial treatment fiber; determining, by theprocessor, computational spatial elements for the target region and forthe location of emitting surfaces of the at least one interstitialtreatment fiber, and a fluence rate for delivering treatment light toeach of the computational spatial elements; determining, by theprocessor, a treatment dose based on the fluence rate, the plurality ofphotosensitizer photokinetic rate parameters, and a photokinetic rateequation; and generating, by the processor, a command for controlling atreatment light source to deliver the treatment dose to the targetregion via the at least one interstitial treatment fiber.

Clause 2: The method of clause 1, wherein information associated withthe target region comprises shape information of the target region, aninitial tissue oxygen concentration for the target region, an initialoxygen flow rate for the target region, and initial optical propertiesfor the target region.

Clause 3: The method of any of the preceding clauses, furthercomprising: determining, by the processor, a value of one or both of aportion of interior volume and a portion of a boundary region of thetarget region to which the delivered treatment dose is greater than thethreshold treatment dose.

Clause 4: The method of clause 3 further comprising: in response to adetermination that the value of one or both of the portion of interiorvolume and the portion of the boundary region of the target region towhich the delivered treatment dose is greater than the thresholdtreatment dose is less than 80%, causing, by the processor, thetreatment light source to increase one or both of therapeutic lightpower and therapeutic treatment time.

Clause 5: The method of any of the preceding clauses, furthercomprising: determining, by the processor, a value of one or both of aportion of interior volume and a portion of a boundary region of thetarget region to which the delivered treatment dose is greater than thethreshold treatment dose and the applied fluence rate is greater thanthe threshold fluence rate.

Clause 6: The method of clause 5, further comprising: in response to adetermination that the value of one or both of the portion of interiorvolume and the portion of the boundary region of the target region towhich the delivered treatment dose is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate, is less than 80%, generating, by the processor,a command for controlling the treatment light source to increase one orboth of therapeutic light power and therapeutic treatment time.

Clause 7: The method of any of the preceding clauses, furthercomprising: determining whether values for one or more of the initialphotosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed.

Clause 8: The method of clause 7, further comprising: in response to adetermination that one or more of the values of the initialphotosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed, determining, by theprocessor, an updated treatment dose based on changed values of the oneor more of the initial photosensitizer concentration, any of theplurality of initial photosensitizer photokinetic rate parameters, aninitial tissue oxygen concentration, initial tissue optical propertiesand an initial oxygen flow rate.

Clause 9: The method of any of the preceding clauses, wherein thecomputational spatial elements comprise tetrahedral mesh elements orvoxel elements.

Clause 10: A system for delivering a treatment dose to a target regionof a patient for interstitial photodynamic therapy, the systemcomprising: a treatment light source coupled to at least oneinterstitial treatment fiber; a diagnostic light source coupled to atleast one interstitial diagnostic fiber; at least one interstitialdetector to detect diagnostic light generated by the diagnostic lightsource and/or treatment light generated by the treatment light sourceand/or photosensitizer fluorescence generated by the diagnostic lightsource or the treatment light source; and a processor configured to:receive information associated with the target region, an initialphotosensitizer concentration, a plurality of initial photosensitizerphotokinetic rate parameters, and a threshold treatment dose for aphotosensitizer, the threshold treatment dose being a thresholdphotodynamic therapy-dose or a threshold reactive oxygen species dose;determine a location in the target region for inserting the at least oneinterstitial treatment fiber to deliver the treatment light; determineinitial values for therapeutic light power, and light emitting lengthand therapeutic treatment time for the at least one interstitialtreatment fiber; determine computational spatial elements for the targetregion and for the location of emitting surfaces of the at least oneinterstitial treatment fiber, and a fluence rate for deliveringtreatment light to each of the computational spatial elements; determinea treatment dose based on the fluence rate, the plurality ofphotosensitizer photokinetic rate parameters, and a photokinetic rateequation; and generate a command for controlling the treatment lightsource to deliver via the at least one interstitial treatment fiber thetreatment dose to the target region.

Clause 11: The system of clause 10, further comprising at least onespectrometer coupled to the at least one interstitial detector to detectone or more of treatment light intensity, diagnostic light intensity andfluorescence light intensity generated by the treatment light source orthe diagnostic light source.

Clause 12: The system of any of clauses 10-11, further comprising aplurality of light-transmitting catheters enclosing the at least oneinterstitial treatment fiber, the at least one interstitial diagnosticfiber and the at least one interstitial detector.

Clause 13: The system of any of clauses 10-12, wherein the treatmentlight source and/or the diagnostic light source comprise a laser or alight emitting diode.

Clause 14: The system of any of clauses 10-13, wherein the processor isfurther configured to determine a value of one or both of a portion ofinterior volume and a portion of a boundary region of the target regionto which the delivered treatment dose is greater than the thresholdtreatment dose.

Clause 15: The system of clause 14, wherein the processor is furtherconfigured to cause, in response to a determination that the value ofone or both of the portion of interior volume and the portion of theboundary region of the target region to which the delivered treatmentdose is greater than the threshold treatment dose is less than 80%, thetreatment light source to increase one or both of therapeutic lightpower and therapeutic treatment time.

Clause 16: The system of any of clauses 10-15, wherein the processor isfurther configured to determine a value of one or both of a portion ofinterior volume and a portion of a boundary region of the target regionto which the delivered treatment dose is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate.

Clause 17: The system of clause 16, wherein the processor is furtherconfigured to generate, in response to a determination that the value ofone or both of the portion of interior volume and the portion of theboundary region of the target region to which the delivered treatmentdose is greater than the threshold treatment dose and the appliedfluence rate is greater than the threshold fluence rate is less than80%, a command for controlling the treatment light source to increaseone or both of therapeutic light power and therapeutic treatment time.

Clause 18: The system of any of clauses 10-17, wherein the processor isfurther configured to: determine whether values for one or more of theinitial photosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed, and in response to adetermination that one or more of the values have changed, determine anupdated treatment dose based on changed values of the one or more of theinitial photosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate.

Clause 19: The system of any of clause 10-18, wherein the computationalspatial elements comprise tetrahedral mesh elements or voxel elements.

Clause 20: The system of any of clauses 10-19, further comprising adisplay configured to enable a user to visualize a two-dimensional orthree-dimensional image of the treatment dose and/or two-dimensional ora three-dimensional image of under- and over-doses overlaid onto atwo-dimensional and/or a three-dimensional image of shape informationfor the target region.

Clause 21: A method for planning an interstitial photodynamic therapytreatment dose to be delivered to a target region of a patient for, themethod comprising: receiving, at a processor, information associatedwith the target region, an initial photo-sensitizer concentration, aplurality of initial photosensitizer photokinetic rate parameters, and athreshold treatment dose for a photosensitizer, the threshold treatmentdose being a threshold photodynamic therapy-dose or a threshold reactiveoxygen species dose; determining a location in the target region forinserting at least one interstitial treatment fiber to deliver thetreatment light; determining, by the processor, initial values fortherapeutic light power, and light emitting length and therapeutictreatment time for the at least one interstitial treatment fiber;determining, by the processor, computational spatial elements for thetarget region and for the location of emitting surfaces of the at leastone interstitial treatment fiber, and a fluence rate for deliveringtreatment light to each of the computational spatial elements; anddetermining, by the processor, a treatment dose based on the fluencerate, the plurality of photosensitizer photokinetic rate parameters, anda photokinetic rate equation.

Clause 22: The method of clause 21, further comprising: determining, bythe processor, a value of one or both of a portion of interior volumeand a portion of a boundary region of the target region to which thedelivered treatment dose is greater than the threshold treatment dose;and determining, in response to a determination that the value is lessthan 80%, an increase in one or more of therapeutic light power, lightemitting length and therapeutic treatment time such that the treatmentdose delivered to at least 80% of one or both of interior volume andboundary region of the target region is greater than the thresholdtreatment dose.

Clause 23: The method of any of clauses 21-22, further comprising:determining whether values for one or more of the initialphotosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed; and determining, inresponse to a determination that one or more of the values have changed,an updated treatment dose based on changed values of the one or more ofthe initial photosensitizer concentration, any of the plurality ofinitial photosensitizer photokinetic rate parameters, an initial tissueoxygen concentration, initial tissue optical properties and an initialoxygen flow rate.

Clause 24: The method of any of clauses 21-23, further comprising:determining whether a location of the at least one interstitialtreatment fiber relative to the target region has changed; anddetermining, in response to a determination that the location haschanged, an updated treatment dose based on the changed location.

Clause 25: The method of any of clauses 21-24, further comprising:determining, by the processor, a value of one or both of a portion ofinterior volume and a portion of a boundary region of the target regionto which the delivered treatment dose is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate; and determining, in response to a determinationthat the value is less than 80%, an increase in one or more oftherapeutic light power, light emitting length and therapeutic treatmenttime such that the treatment dose delivered to at least 80% of one orboth of interior volume and boundary region of the target region isgreater than the threshold treatment dose and the applied fluence rateis greater than the threshold fluence rate.

Clause 26: A system for planning an interstitial photodynamic therapy,the system comprising: a non-transitory computer-readable memory tostore instructions; and a processor to execute the instructions storedon the memory, the instructions causing the processor to: receiveinformation associated with the target region, an initialphotosensitizer concentration, a plurality of initial photosensitizerphotokinetic rate parameters, and a threshold treatment dose for aphotosensitizer, the threshold treatment dose being a thresholdphotodynamic therapy-dose or a threshold reactive oxygen species dose;determine a location in the target region for inserting at least oneinterstitial treatment fiber to deliver the treatment light; determineinitial values for therapeutic light power, and light emitting lengthand therapeutic treatment time for the at least one interstitialtreatment fiber; determine computational spatial elements for the targetregion and for the location of emitting surfaces of the at least oneinterstitial treatment fiber, and a fluence rate for deliveringtreatment light to each of the computational spatial elements; anddetermine a treatment dose based on the fluence rate, the plurality ofphotosensitizer photokinetic rate parameters, and a photokinetic rateequation.

Clause 27: The system of clause 26, further comprising at least onespectrometer coupled to the at least one interstitial detector to detectone or more of treatment light intensity, diagnostic light intensity andfluorescence light intensity generated by a treatment light source or adiagnostic light source.

Clause 28: The system of any of clauses 26-27, further comprising aplurality of light-transmitting catheters enclosing the at least oneinterstitial treatment fiber, at least one interstitial diagnostic fiberand/or at least one interstitial detector.

Clause 29: The system of any of clauses 26-28, further comprising atreatment light source and/or a diagnostic light source, each of whichcomprise a laser or a light emitting diode.

Clause 30: The system of clause 26, wherein the processor is furtherconfigured to determine a value of one or both of a portion of interiorvolume and a portion of a boundary region of the target region to whichthe delivered treatment dose is greater than the threshold treatmentdose.

Clause 31: The system of clause 30, wherein the processor is furtherconfigured to determine, in response to a determination that the valueof one or both of the portion of interior volume and the portion of theboundary region of the target region to which the delivered treatmentdose is greater than the threshold treatment dose is less than 80%, anincrease in one or more of therapeutic light power, light emittinglength and therapeutic treatment time such that at least 80% of theinterior volume and/or the boundary region of the target region receivesa treatment dose greater than the threshold treatment dose.

Clause 32: The system of any of clauses 26-31, wherein the processor isfurther configured to determine a value of one or both of a portion ofinterior volume and a portion of a boundary region of the target regionto which the delivered treatment dose is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate.

Clause 33: The system of clause 32, wherein the processor is furtherconfigured to determine, in response to a determination that the valueof one or both of the portion of interior volume and the portion of theboundary region of the target region to which the delivered treatmentdose is greater than the threshold treatment dose and the appliedfluence rate is greater than the threshold fluence rate is less than80%, an increase in one or more of therapeutic light power, lightemitting length and therapeutic treatment time such that at least 80% ofthe interior volume and/or the boundary region of the target regionreceives a treatment dose greater than the threshold treatment dose anda fluence rate is greater than the threshold fluence rate.

Clause 34: The system of any of clauses 26-33, wherein the processor isfurther configured to: determine whether values for one or more of theinitial photosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed, and in response to adetermination that one or more of the values have changed, determine anupdated treatment dose based on changed values of the one or more of theinitial photosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate.

Clause 35: The system of any of clauses 26-34, wherein the computationalspatial elements comprise tetrahedral mesh elements or voxel elements.

Clause 36: The system of any of clauses 26-35, further comprising adisplay configured to enable a user to visualize a two-dimensional orthree-dimensional image of the treatment dose and/or a two-dimensionalor three-dimensional image of under- and over-doses overlaid onto atwo-dimensional and/or three-dimensional image of shape information forthe target region.

Clause 37: A non-transitory machine-readable medium storing instructionsto cause one or more processors to perform operations comprising:receiving, at a processor, information associated with the targetregion, an initial photo-sensitizer concentration, a plurality ofinitial photosensitizer photokinetic rate parameters, and a thresholdtreatment dose for a photosensitizer, the threshold treatment dose beinga threshold photodynamic therapy-dose or a threshold reactive oxygenspecies dose; determining a location in the target region for insertingat least one interstitial treatment fiber to deliver the treatmentlight; determining, by the processor, initial values for therapeuticlight power, and light emitting length and therapeutic treatment timefor the at least one interstitial treatment fiber; determining, by theprocessor, computational spatial elements for the target region and forthe location of emitting surfaces of the at least one interstitialtreatment fiber, and a fluence rate for delivering treatment light toeach of the computational spatial elements; and determining, by theprocessor, a treatment dose based on the fluence rate, the plurality ofphotosensitizer photokinetic rate parameters, and a photokinetic rateequation.

Clause 38: The non-transitory machine-readable medium of clause 37,wherein information associated with the target region comprises shapeinformation of the target region, an initial tissue oxy-genconcentration for the target region, an initial oxygen flow rate for thetarget region, and initial optical properties for the target region.

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

As used herein, the term “about” preceding a quantity indicates avariance from the quantity. The variance may be caused by manufacturingtolerances or may be based on differences in measurement techniques. Thevariance may be up to 10% from the listed value in some instances. Thoseof ordinary skill in the art would appreciate that the variance in aparticular quantity may be context dependent and thus, for example, thevariance in a dimension at a micro or a nano scale may be different thanvariance at a meter scale.

As used herein, the phrase “at least one of” preceding a series ofitems, with the term “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one of each item listed; rather, the phrase allows a meaningthat includes at least one of any one of the items, and/or at least oneof any combination of the items, and/or at least one of each of theitems. By way of example, the phrases “at least one of A, B, and C” or“at least one of A, B, or C” each refer to only A, only B, or only C;any combination of A, B, and C; and/or at least one of each of A, B, andC.

Terms such as “top,” “bottom,” “front,” “rear” and the like as used inthis disclosure should be understood as referring to an arbitrary frameof reference, rather than to the ordinary gravitational frame ofreference. Thus, a top surface, a bottom surface, a front surface, and arear surface may extend upwardly, downwardly, diagonally, orhorizontally in a gravitational frame of reference.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

What is claimed is:
 1. A method of administering interstitialphotodynamic therapy by delivering treatment dose to a target region ofa patient, the method comprising: receiving, at a processor, informationassociated with the target region, an initial photosensitizerconcentration, a plurality of initial photosensitizer photokinetic rateparameters, and a threshold treatment dose for a photosensitizer, thethreshold treatment dose being a threshold photodynamic therapy-dose ora threshold reactive oxygen species dose; determining a location in thetarget region for inserting at least one interstitial treatment fiber todeliver the treatment light; determining, by the processor, initialvalues for therapeutic light power, and light emitting length andtherapeutic treatment time for the at least one interstitial treatmentfiber; determining, by the processor, computational spatial elements forthe target region and for the location of emitting surfaces of the atleast one interstitial treatment fiber, and a fluence rate fordelivering treatment light to each of the computational spatialelements; determining, by the processor, a treatment dose based on thefluence rate, the plurality of photosensitizer photokinetic rateparameters, and a photokinetic rate equation; determining, by theprocessor, a value of one or both of a portion of interior volume and aportion of a boundary region of the target region to which the deliveredtreatment dose is greater than the threshold treatment dose; andgenerating, by the processor, a command for controlling a treatmentlight source to deliver the treatment dose to the target region via theat least one interstitial treatment fiber.
 2. The method of claim 1,wherein information associated with the target region comprises shapeinformation of the target region, an initial tissue oxygen concentrationfor the target region, an initial oxygen flow rate for the targetregion, and initial optical properties for the target region.
 3. Themethod of claim 1, further comprising: in response to a determinationthat the value of one or both of the portion of interior volume and theportion of the boundary region of the target region to which thedelivered treatment dose is greater than the threshold treatment dose isless than 80%, causing, by the processor, the treatment light source toincrease one or both of therapeutic light power and therapeutictreatment time.
 4. The method of claim 1, further comprising:determining, by the processor, a value of one or both of a portion ofinterior volume and a portion of a boundary region of the target regionto which the delivered treatment dose is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate.
 5. The method of claim 4, further comprising: inresponse to a determination that the value of one or both of the portionof interior volume and the portion of the boundary region of the targetregion to which the delivered treatment dose is greater than thethreshold treatment dose and the applied fluence rate is greater thanthe threshold fluence rate, is less than 80%, generating, by theprocessor, a command for controlling the treatment light source toincrease one or both of therapeutic light power and therapeutictreatment time.
 6. The method of claim 1, further comprising:determining whether values for one or more of the initialphotosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed.
 7. The method of claim 6,further comprising: in response to a determination that one or more ofthe values of the initial photosensitizer concentration, any of theplurality of initial photosensitizer photokinetic rate parameters, aninitial tissue oxygen concentration, initial tissue optical propertiesand an initial oxygen flow rate for the target region have changed,determining, by the processor, an updated treatment dose based onchanged values of the one or more of the initial photosensitizerconcentration, any of the plurality of initial photosensitizerphotokinetic rate parameters, an initial tissue oxygen concentration,initial tissue optical properties and an initial oxygen flow rate. 8.The method of claim 1, wherein the computational spatial elementscomprise tetrahedral mesh elements or voxel elements.
 9. A method forplanning an interstitial photodynamic therapy treatment dose to bedelivered to a target region of a patient for, the method comprising:receiving, at a processor, information associated with the targetregion, an initial photosensitizer concentration, a plurality of initialphotosensitizer photokinetic rate parameters, and a threshold treatmentdose for a photosensitizer, the threshold treatment dose being athreshold photodynamic therapy-dose or a threshold reactive oxygenspecies dose; determining a location in the target region for insertingat least one interstitial treatment fiber to deliver the treatmentlight; determining, by the processor, initial values for therapeuticlight power, and light emitting length and therapeutic treatment timefor the at least one interstitial treatment fiber; determining, by theprocessor, computational spatial elements for the target region and forthe location of emitting surfaces of the at least one interstitialtreatment fiber, and a fluence rate for delivering treatment light toeach of the computational spatial elements; determining, by theprocessor, a treatment dose based on the fluence rate, the plurality ofphotosensitizer photokinetic rate parameters, and a photokinetic rateequation; determining, by the processor, a value of one or both of aportion of interior volume and a portion of a boundary region of thetarget region to which the delivered treatment dose is greater than thethreshold treatment dose; and determining, in response to adetermination that the value is less than 80%, an increase in one ormore of therapeutic light power, light emitting length and therapeutictreatment time such that the treatment dose delivered to at least 80% ofone or both of interior volume and boundary region of the target regionis greater than the threshold treatment dose.
 10. The method of claim 9,further comprising: determining whether values for one or more of theinitial photosensitizer concentration, any of the plurality of initialphotosensitizer photokinetic rate parameters, an initial tissue oxygenconcentration, initial tissue optical properties and an initial oxygenflow rate for the target region have changed; and determining, inresponse to a determination that one or more of the values have changed,an updated treatment dose based on changed values of the one or more ofthe initial photosensitizer concentration, any of the plurality ofinitial photosensitizer photokinetic rate parameters, an initial tissueoxygen concentration, initial tissue optical properties and an initialoxygen flow rate.
 11. The method of claim 9, further comprising:determining whether a location of the at least one interstitialtreatment fiber relative to the target region has changed; anddetermining, in response to a determination that the location haschanged, an updated treatment dose based on the changed location. 12.The method of claim 9, further comprising: determining, by theprocessor, a value of one or both of a portion of interior volume and aportion of a boundary region of the target region to which the deliveredtreatment dose is greater than the threshold treatment dose and theapplied fluence rate is greater than the threshold fluence rate; anddetermining, in response to a determination that the value is less than80%, an increase in one or more of therapeutic light power, lightemitting length and therapeutic treatment time such that the treatmentdose delivered to at least 80% of one or both of interior volume andboundary region of the target region is greater than the thresholdtreatment dose and the applied fluence rate is greater than thethreshold fluence rate.